Eur J Appl Physiol (2007) 101:143–194

DOI 10.1007/s00421-007-0474-z

REVIEW ARTICLE

From space to Earth: advances in human physiology

from 20 years of bed rest studies (1986–2006)
A. Pavy-Le Traon Æ M. Heer Æ M. V. Narici Æ
J. Rittweger Æ J. Vernikos

Accepted: 13 April 2007 / Published online: 28 July 2007

Springer-Verlag 2007

Abstract Bed rest studies of the past 20 years are re- reduction in plasma volume which leads to a now well-
viewed. Head-down bed rest (HDBR) has proved its use- documented set of cardiovascular changes including
fulness as a reliable simulation model for the most changes in cardiac performance and baroreflex sensitivity
physiological effects of spaceflight. As well as continuing that are identical to those in space. Calcium excretion is
to search for better understanding of the physiological increased from the beginning of bed rest leading to a sus-
changes induced, these studies focused mostly on identi- tained negative calcium balance. Calcium absorption is
fying effective countermeasures with encouraging but reduced. Body weight, muscle mass, muscle strength is
limited success. HDBR is characterised by immobilization, reduced, as is the resistance of muscle to insulin. Bone
inactivity, confinement and elimination of Gz gravitational density, stiffness of bones of the lower limbs and spinal
stimuli, such as posture change and direction, which affect cord and bone architecture are altered. Circadian rhythms
body sensors and responses. These induce upward fluid may shift and are dampened. Ways to improve the process
shift, unloading the body’s upright weight, absence of work of evaluating countermeasures—exercise (aerobic, resis-
against gravity, reduced energy requirements and reduction tive, vibration), nutritional and pharmacological—are
in overall sensory stimulation. The upward fluid shift by proposed. Artificial gravity requires systematic evaluation.
acting on central volume receptors induces a 10–15% This review points to clinical applications of BR research
revealing the crucial role of gravity to health.

A. Pavy-Le Traon (&) Keywords Bed rest
Countermeasures
Fluid shift

Service D’explorations Fonctionnelles Respiratoires Et Skeletal muscle
Bone
Calcium
Metabolism

d’analyses Physiologiques, Hopital La Cavale Blanche, Space flight
Health benefits
University Hospital of Brest, 29609 Brest Cedex, France
e-mail: [email protected]

A. Pavy-Le Traon Introduction

Medes, Institut de Médecine et de Physiologie Spatiales,
Hopital Rangeuil, 31405 Toulouse Cedex 4, France
The history of bed rest predates spaceflight. Before the
M. Heer nineteenth century, periods of prolonged bed rest due to
Deutsches Zentrum fuer Luft- und Raumfahrt (DLR), illness usually meant losing a job or livelihood. Therefore,
Institute of Aerospace Medicine, 51147 Koeln, Germany bed rest as a means to treat disease was usually avoided.
This changed in the nineteenth century, when bed rest was
M. V. Narici
J. Rittweger
Institute for Biophysical and Clinical Research into Human first introduced as a medical treatment. Any adverse con-
Movement, Manchester Metropolitan University, sequences of this commonly applied therapy were attributed
Alsager Campus, Hassall Road, to the medical condition that sent one to bed in the first
Cheshire ST7 2HL Cheshire, UK
place. A lack of recovery was assumed to be an inevitable
J. Vernikos result of the illness. A few noted that perhaps rest was not
Thirdage llc, Culpeper, VA, USA the cure for everything, but their voices went unheeded.

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144 Eur J Appl Physiol (2007) 101:143–194

Then an enlightened team of clinicians made an inter- were reviewed and published in 1986 in the book, Inac-
esting observation. During the polio epidemic of the first tivity: physiological effects (Sandler and Vernikos 1986).
half of the twentieth century and until the Salk vaccine The title Inactivity of this first review denotes the focus
became available in the 1950s, every summer brought an of earlier studies on the role of inactivity resulting from bed
outbreak of polio somewhere in the world. Franklin D. rest, and, in fact, from spaceflight. This focus also drove
Roosevelt was the best known victim of this infection, the overwhelming emphasis on the search for exercise
which results in crippling paralysis of the muscles. Don countermeasures to restore normal physiological function.
Whedon and his group (Dietrick et al. 1948) studying the However, it became apparent that it is not only activity that
bone loss in polio victims wondered whether the increased is reduced in bed rest and in flight. A multitude of exercise
excretion of calcium was due to the disease or the resulting countermeasures tested has proven only partially effective.
immobilization and inactivity. They did an experiment to In addition, it soon became apparent that the reduced
try and answer this question. Medical students who were influence of gravity in addition to inactivity, affected the
otherwise healthy were placed in bed for 30 days with circulation and fluid and electrolyte balance that relied on
lower body casts. Sure enough, just like the polio victims, postural change, the loading of vertical body weight for
they showed increased excretion of calcium and loss of healthy bone structure, reduced acceleration stimuli and
bone density in their legs demonstrating in healthy persons altered directional input that affected the vestibular and
for the first time that lying in bed immobile was not so proprioceptive systems regulating balance and coordina-
good for one’s health. Doctors observed during World War tion, emotional and endocrine factors due to the relative
II that men who were made ambulatory soon after surgery confinement, to name a few. These observations expanded
or injury, recovered faster than those who remained in bed the search into the physiological mechanisms responsible
to recover. The last half of the twentieth century finally saw for the composite of changes resulting during and follow-
a gradual reversal of the practice of using bed rest as ing bedrest and opened up new approaches for exploring
medical treatment. The significance of these observations comprehensive, more effective countermeasures.
took time, mostly because it is not easy to reverse an Unfortunately, very few attempts at integrated studies
established practice and most observations were normally have been made. A broader set of parameters may have been
made in sick people whose basic illness complicated if not measured but the rationale and interpretation of results con-
the findings, certainly the interpretation. Thus, one of the tinued to follow traditional analyses of individual systems.
first known observations from research supporting human Fortunately, in the past few years, efforts into true
spaceflight made its way as an application in general integration have been encouraged with promising results
practice on Earth. and novel approaches in the search for countermeasures
have emerged. Examples include the combinations of
Bed rest studies in the space era: reduced pull of gravity exercise and nutrition, exercise within a lower body neg-
or inactivity? ative pressure (LBNP) chamber, foot vibration with and
without nutritional interventions, a few pharmacological
With the advent of human spaceflight in 1961, immersion approaches and even attempts at rekindling interest in
in water was used as a logical model for reducing the pull artificial gravity. Most of these have focused on preventing
of gravity on the mass of the body. But it soon proved or correcting predominantly cardiovascular, but muscle or
impractical because remaining in water for more than a day bone deficits as well, but rarely all three. For that reason, a
brought on unpleasant consequences. Then Whedon’s detailed discussion will be found under each specific sys-
(Dietrick et al. 1948) earlier observations found application tem section with a summary at the end of this review.
in space research. Whedon predicted that astronauts in In the early 1970s, cosmonauts returning from longer
space were in essence inactive and would, like his immo- missions complained to their medical staff that on their
bilized students, also lose bone calcium. In the near-total return from space they had a hard time sleeping because
absence of gravity in space they would not need to use their they had the sensation that they were slipping off the foot
lower limbs to support their body’s weight. A few earlier of the bed. They tried to correct the situation by raising the
studies used chair sitting for up to 3 days, to study the foot of the bed until it felt horizontal and they could get
effect of inactivity. But placing healthy volunteers in bed back to sleep. Every night they lowered the foot of the bed
became the model of choice for inducing and studying the a little until lying horizontal felt normal again. Russian
effects of prolonged spaceflight and for testing potential researchers took note of this observation and surmised that
countermeasures. perhaps the head-down position on Earth was closer to
The first 25 years of the studies using bed rest as a what it felt like to be in space. The head-down bed rest
simulation model for inducing the effects of spaceflight (HDBR) simulation model was born.

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The Soviets tested –15, –10 and –5 for comfort, Bed rest of course does not eliminate the Gx gravita-
acceptability and magnitude of response and decided –6 tional influence. In fact, bed rest increases threefold or at
was the best compromise (Atkov and Bednenko 1992). In least doubles the number of hours spent per day in the Gx
1977/1978 joint USA/USSR 7-day studies done both at the orientation. Because we do not know what its role may be,
IMBP in Moscow and ARC in California, compared HDBR does not mean it has no effect. It could provide only the
with horizontal bed rest and confirmed the added value of change signal to Gz or it is tempting to speculate that it
HDBR. Maximal exercise response, LBNP and +3 Gz may be involved in some way in sleep. Norsk et al. (1998)
(head to toe G-stress) tolerance were used as the end-points and Norsk (2005) attributed the more pronounced decrease
of deconditioning. in intra-vascular volume in spaceflight than that induced by
In many ways, HDBR made it in fact more comfortable HDBR, which results in the stimulation of fluid-retaining
for the subjects. They could lean over the side of the bed to mechanisms, to the total abolition of the G-stress in flight.
eat. They could raise their knees as well since that only He inferred that the difference was due to the presence of
increased the head-ward fluid shift. In the past 20 years the Gx during bed rest. Removal of both Gz and Gx stimuli
almost all bed rest studies have been done in the head- can only be achieved in space or possibly reduced in the
down position. dry immersion bed rest model.
How the first day of BR (BR 1) begins is frequently not It has been argued that bed rest is not a good model for
mentioned in published paper methodology, but can make spaceflight. That is a true statement from an operational
all the difference to the time course and magnitude of point of view. Studies do not include activities surrounding
changes. This is particularly true if the duration of the study launch, acceleration, excitement, followed by confinement
is relatively short. There are very good scientific reasons for and isolation of a group in very small living quarters nor to
using HDBR especially if on BR1 the subject goes from environmental parameters such as light and pressure in the
standing upright to head down, in other words uses the spacecraft. The conditions during the first couple of days
maximum postural change to mark the beginning of bed rest. require adjustment to the conflict in visual and vestibular
The Russians went on to improve on HDBR by devel- systems due to the absence of the usual directional cues and
oping a dry immersion bed—a soft waterbed that envelops may result in what has become known as space motion
the body and presumably reduces even the Gx (transverse sickness. Only a few studies have included reentry accel-
G-Stress) influence. Only a limited number of such beds eration profiles. Nevertheless, depending on the care with
exist and Russian and Scandinavian scientists are the only which these studies are done, HDBR is the best model we
ones who have used this model. have on Earth for inducing the effects of microgravity in
order to study them. It is particularly the best simulation
HDBR studies: value as a simulation model model for evaluating countermeasures to most of the
physiological effects of spaceflight.
Bed rest studies produced and continue to generate a It had been the custom among those running bed rest
wealth of data on the physiological effects of bed rest in studies in the early days to call ‘bed rest day one’ (BR1) a
healthy individuals, its clinical implications and the day when subjects did not get out of bed after waking up
importance of activity to health. but continued to stay in bed. This produced a very gradual
A more comprehensive understanding has emerged in response. When HDBR studies became popular, subjects
the past 20 years of the complex nature and variety of ways were allowed to get out of bed in the morning, shower, eat
that reduction of Gz gravitational stimuli affect body sen- breakfast while the foot of the bed was raised by about
sors and responses when lying continuously in the hori- 15 in. producing the head-down angle of –6. Subjects
zontal position or in HDBR. These include for example, the would then go back to bed at 9 A.M. to begin BR1. This
upward shift of body fluids, the absence of changes in routine produces a maximum possible posture change (1–
posture, unloading of the body’s upright weight, the ab- 0 Gz), inducing a full head-ward fluid shift that triggers a
sence of working against the force of gravity, reduced significant and consistent sequence of events lasting about
energy requirements, the absence of linear acceleration 24 h, leading subsequently to all the changes we have
(except during tests or transportation), reduced proprio- become so familiar with. If one stays in bed on awakening
ceptive stimulation, altered social interactive and work/rest on BR1, and the foot of the bed is merely raised to the –6
cues and a reduction in overall sensory stimulation. angle, the initial physiological response is dampened. No
The consequences of the absence or reduction of these significant cardiovascular and endocrine changes occur
gravitational stimuli directly or indirectly affect every during the first 24 h of bed rest that would normally
organ in the body. accompany the maximal postural change.

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Similarities of the physiological effects of HDBR Post-flight Post-bed rest

and space flight
Maximal aerobic capacity fl ±12% fl 20–25%
As a result of this upward shift of fluid, the loss of fluid and Orthostatic hypotension › ›
sodium (Na) in the urine led to a 10–15% reduction in plasma Balance/stability fl fl
volume depending on the duration of the study and the Coordination/gate Poor/wide Poor
method used. This reduction in PV leads to a now well- Adapted from Nicogossian et al. (1994)
documented set of cardiovascular changes including changes
in cardiac performance and baroreflex sensitivity and re-
duced aerobic capacity that are identical to those in space. Factors affecting the results
Convertino (1995) carried out a very thorough comparative
analysis of the cardiovascular responses demonstrating these Considering how important the elimination of posture
similarities. Such thorough reviews and comparative analy- change by bed rest is to the fidelity of the results to
ses have not been done for other systems and should be. microgravity, it is amazing that published papers may not
Calcium (Ca) excretion is increased from the beginning mention the position in which tests are performed. Closer
of bed rest leading to a sustained negative calcium balance. scrutiny may reveal that plasma volume was measured in
Calcium absorption through the gut is reduced. Body the seated position, or that subjects were allowed to use the
weight, muscle mass, muscle strength are reduced, as is the bathroom. Other reports state that subjects used a bedside
resistance of muscle to insulin. Bone density, stiffness of pot—standing from squatting is an excellent orthostatic
bones of the lower limbs and spinal cord and bone archi- test—or sat on a bedpan on the bed, presumably as an
tecture are all altered. Circadian rhythms may shift and are acceptable compromise.
dampened. Both in bed rest and spaceflight subjects com- Along the same lines, papers may report results of flight
plain of poor sleep even though EEG records appear to be experiments or bed rest studies as if their experiment was
generally normal. the only one conducted in these individuals. The possibil-
On return from space or reambulating after HDBR, ity, indeed the certainty, that their results may have been
subjects show a high incidence of orthostatic hypotension, affected by some other test or housekeeping activity seems
balance problems, wider short steps and foot dragging to be ignored.
occasionally, poor coordination, as well as very tender In addition, non-gravitational aspects of this research
soles of the feet. All these changes depend on neural, such as confinement and the environment could alter the
neurohumoral and humoral mechanisms that are affected in physiological baseline through anxiety, loneliness, un-
very similar ways in both HDBR and spaceflight. wanted interaction with staff or strangers or lack of pri-
A comparison of physiological changes induced in space vacy. All or any of these could affect the results. The
flight and in bed rest is given in the table hereafter. interactive influence of reduced gravity stimuli and con-
finement has received very little attention.
Other factors that may interfere with the results of a bed
rest study but that are transparent to an investigator include
Space Bed rest (HDBR)
clinical aspects of a study. For instance, a mild laxative
Height › ± 1.3 cm › ± 1.0 cm may routinely be prescribed. Those that work by drawing
Body mass/weight fl 3–4% fl 2–4% fluid into the gut to soften stools may well interfere with
Maximal aerobic capacity Not measured fl 25% the results. Headaches often of a sinus nature are not
Plasma volume fl 10–15% fl 10–15% uncommon. Headaches may also be triggered by overhead
Urinary calcium › › lighting. Light intensity, light/dark cycles and wavelength
Bone density fl 1.6%/month fl 0.5–1%/month can all affect circadian rhythms and therefore results.
Absorption of Ca from Gut fl fl Dietary consistency and control is of paramount
Renal stone risk › › importance to the reliability of the results.
Muscle mass fl fl The social environment, visitors, communication with
Muscle strength fl fl
the outside world and access to news can all become
Insulin resistance › ›
sources of comfort or irritation. Staff has a tendency to
Nausea/sickness/vertigo None 35% Vertigo 10%
treat anyone horizontal as a patient bringing on patient-like
behaviour. Medical staff may not differentiate between
Severe 7% Nausea rarely present
physiological adaptation of a healthy volunteer in bed, and
Moderate 23%
a medical condition that may indeed require treatment.
Mild 35%
Attitude of staff may lack sensitivity to the captive status of

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subjects, such as cheerfully waving goodbye at the end of ulate the physiological effects of weightlessness, in par-
their day when subjects are stuck in bed. ticular on the cardiovascular system and body fluid
There is evidence that the attitude of a subject to the regulation. Some cardiovascular changes are well docu-
study may make the difference in high or low circulating mented and reviewed by Sandler and Vernikos (1986).
cortisol levels during bed rest. Unchecked high cortisol Most experiments since 1986 were performed using the –6
levels can exacerbate bone loss and muscle wasting as well HDBR model, in male volunteers.
as interfere with many other physiological functions. High Bed rest induces a fluid shift from the lower to the
cortisol levels may be controlled by conducting studies in upper part of the body (Fig. 1a, b). This fluid shift results
dedicated facilities with staff used to supporting bed rest in a transient increase of plasma volume as more fluid
studies in healthy volunteers and by pairing rookie with moves into the vascular compartment from the lower
experienced subjects. body than that is filtered out of capillaries into the upper
For these and probably other reasons results from bed body (Atkov and Bednenko 1992; Gharib et al. 1988;
rest studies carried out in different facilities with teams Greenleaf 1984). This thoraco-cephalic fluid shift to-
who lack experience in such studies may not be entirely gether with the plasma volume expansion stimulate
comparable. central volume carotid, aortic and cardiac receptors
inducing an increase in diuresis and natriuresis and a
Testing or countermeasure? decrease in plasma volume. As in spaceflight, cardio-
vascular deconditioning characterised by orthostatic
Last but not least the experimental design itself will alter intolerance and reduced exercise capacity is observed at
the outcome. This is not only true when multiple investi- the end of bed rest (Fig. 1a, b).
gations are incorporated into one set of subjects but can
also hold true when an investigator becomes over-ambi-
tious or makes assumptions about the sequence of testing.
Most investigators wish to test on the last two days of bed a
rest and/or the first day after it ends. This results in a
barrage of tests that challenge exactly those systems that
were expected to be deconditioned by bed rest.
This was first observed in 1979 when during a bed rest
study horizontal maximum aerobic capacity was followed by
LBNP to tolerance, followed by +3 Gz acceleration tolerance
on these last three successive days. No reduction in tolerance
was observed either with the LBNP or the acceleration tests.
Many years later Engelke et al. (1996) showed how a single
maximal bout of exercise was an effective countermeasure
for orthostatic intolerance after 16 days of HDBR.

Concluding remarks b

Ground research using bed rest has yielded a better under-

standing of the mechanisms that bring about the changes
induced by living in the microgravity of space. It also
provides the best available means for evaluating counter-
measure effectiveness needed to enable and ensure crew
performance and safety on long duration missions. This
review picks up where Inactivity: Physiological Effects
(Sandler and Vernikos 1986) left off and extends the review
of bed rest studies to cover the past 20 years of research.
Fig. 1 This shows the fluid shift from the lower to the upper part of
the body induced by real (a) and simulated weightlessness (b). This
Cardiovascular and pulmonary adaptation thoraco-cephalic fluid shift stimulates central volume carotid, aortic
and cardiac receptors inducing an increase in diuresis and natriuresis
and a decrease in plasma volume. As in spaceflight, cardiovascular
Bed rest, ranging from several hours to several weeks or deconditioning characterised by orthostatic intolerance is observed at
months, has been the model most frequently used to sim- the end of bed rest

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This section reviews the results published in the past As for methodology, impedance plethysmography has
20 years on the changes in cardiovascular function and the been used to monitor minimal alterations in TBW (Schel-
underlying physiological mechanisms induced by bed rest. tinga et al. 1991) and to quantify the extent of the fluid
redistribution in the body in a manner that corresponds well
Body fluid regulation in bed rest with anthropometric determinations (Montgomery 1993).
With this technique, Montgomery showed that –6 HDBR
The thoraco-cephalic fluid shift with an accompanying produces a larger and more persistent thoracic fluid shift
diuresis and natriuresis at the beginning of spaceflight was than horizontal bed rest. Antiorthostatic thoracic volume
suggested to be the main cause for body fluid and body- changes were found to closely approximate those estimated
mass losses in spaceflight (Moore and Thornton 1987; to take place in flight while leg volume changes were much
Thornton et al. 1987). But, several space missions have smaller than those observed in flight. Multifrequency
shown that conclusions drawn from HDBR studies are not impedance techniques have been proposed as tools for the
totally transferable to space. It has been shown in the non-invasive monitoring of segmental body fluid volumes
MIR-92-, D2-, SLS-1/SLS-2 missions that no diuresis in spaceflights and HDBR (Drummer et al. 2000a, b).
occurred in astronauts when entering microgravity However, this technique still needs further validation and
(Drummer et al. 1993; Drummer et al. 2000a; Leach et al. some authors reported limitations. Bartok et al. (2003)
1996). Pre-mission treatment like sauna sessions, de- compared bioelectrical impedance spectroscopy (BIS) to
creased fluid intake and application of diuretics might assess extra-cellular water (ECW), intra-cellular water
support these findings of balanced fluid homeostasis at the (ICW) and TBW to deuterium and bromide dilution tech-
beginning of spaceflight. Although metabolic fluid bal- niques. In a first study, the technique accurately followed
ances were calculated during the D-2 mission resulting in the within-individual change in body water compartments.
balanced total body fluid, further studies are mandatory But in a second study performed by the same investigators,
mimicking the treatments before space missions to this technique failed to measure the ICW independently of
underline these findings. ECW and TBW. The authors concluded that limitations in
Several experiments have been performed to assess the precision and insensitivity to acute changes in ICW mea-
effect of HDBR on body fluid redistribution along the body suring techniques warrant further validation studies before
axis and its different compartments. It has been shown that using this technique as a reliable method to assess fluid
the total body fluid loss is for one part derived from the movements and nutritional status.
extra-vascular space, and for the other part from the intra- The kinetics of the plasma volume (PV) and hormonal
vascular space; Drummer et al. (2000b) showed it in a changes with HDBR have been described at length.
well-controlled 6-day bed rest study (crossover design, Changes in PV have been measured directly (using dyes for
identical diet, constant and controlled sodium and fluid instance) or indirectly (derived from Hct and Hb changes;
51
intake), by using a multifrequency impedance technique. In Cr-technique). Maillet et al. (1994) measured the initial
a 28-day HDBR, Fortney et al. (1991) used serial isotope changes. They reported a maximal increase in PV of 9.2%
measurements to measure body fluid responses and con- after 6.5 h. After 2 days of HDBR, Johansen et al. (1997)
cluded that during the early part of bed rest, total body found a decrease in PV of 6.1%. Other studies confirmed
water (TBW) loss was mostly from the extra-cellular vol- this rapid decrease to be around 10% after 4 days (Sigaudo
ume (ECV), and thereafter, the TBW deficit was derived et al. 1996) and 7 days (Custaud et al. 2002). No major
from the intracellular compartment. Blanc et al. (1998) further decrease in PV was recorded with longer bed rest of
used the double-labelled water method to measure TBW, 16 days (–15%) (Blanc et al. 1998) and 28 days (–11%)
water turnover and metabolic water formation, as well as (Maillet et al. 1996). During a 42-day HDBR, Johansen
total energy expenditure, before and at the end of a 42-day et al. (1997) demonstrated the usefulness of indirect mea-
HDBR. HDBR resulted in a significant reduction in body surements; PV measured by the Evans blue dye dilution
weight (2%), TBW (5%), and lean body mass (4%), but fat technique decreased by 9.6 ± 2.2% on the 42nd day rela-
mass (DEXA measurements) and water turnover did not tive to that of the acute supine, horizontal position. Based
change. Segmental body composition showed decreased on changes in Hct and Hb, PV decrease was 10.2 ± 3.2%
lean body mass in the legs and trunk. The hydration of lean (Fig. 2). Others have found this indirect technique to be
body mass did not change. Because they had only obtained reasonably reliable if comparisons are made within the
two data points, the authors concluded that no relevant same day but less so when comparing changes from day to
modifications in water metabolism were triggered during day. This may account for discrepancies in some reports of
the prolonged HDBR period. This example emphasises the PV changes. For instance, Belin de Chantemele et al.
importance of studying the time course of physiological (2004a) reported a smaller decrease in PV measured indi-
adaptive changes. rectly after 90 days of HDBR (–4.7 ± 1.8%) though these

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rhythms of PRA (–6 HDT period) that had been previ-

ously observed by Gharib et al. (1992).
Haruna et al. (1997) conducted two horizontal bed rest
studies of 20 days in 18 male subjects. PRA and aldoste-
rone were also consistently increased during bed rest but
angiotensin II was increased only during the early days. In
a 28-day HDBR (–6) study in men (Maillet et al. 1996), on
a controlled diet of 140 mmol Na+ and 70 mmol of K+,
PRA and aldosterone increased by more than 60%. In the
same study, ANP decreased by more than 30% whereas
norepinephrine and epinephrine were unchanged. On the
other hand, Maillet et al. (2000) found in a 120-day HDBR
study with women an increase in ANP throughout HDBR,
while circulating aldosterone increased and remained ele-
Fig. 2 Relative changes in plasma volume (n = 5–7) during 42 days vated.
of 6 HDBR compared with a horizontal, supine control subject
From these different studies, the changes in the renin-
before and after HDBR derived from either Evans blue dilution (EB)
(n = 6) or changes in haematocrit and haemoglobin (n = 7). angiotensin-aldosterone system showed an increase in PRA
#Significant difference (P < 0.05) compared with values before with bed rest and a decrease in the aldosterone/PRA ratio.
HDBR (from Johansen et al. 1997) Aldosterone also increased (Schmedtje et al. 1996; Haruna
et al. 1997; Maillet et al. 2000) or remained stable with a
same investigators also reported a decrease in TBW of high average salt intake (Schmedtje et al. 1996; Grenon
6.3 ± 5.4%. et al. 2004a). After an initial increase, ANP generally de-
Standardisation of methods and the reference position of creased with HDBR. Changes in epinephrine and norepi-
the subject when plasma volume is measured are of para- nephrine are more variable, non-significant or characterised
mount importance. by a decrease in norepinephrine, in particular in long
duration HDBR (Gharib et al. 1992; Sigaudo et al. 1998).
Volume regulating hormones Changes in AVP are also more variable with no change or
an increase with HDBR, possibly related to different
Hormone changes induced by fluid shifts have been studied hydration conditions of the volunteers.
extensively during HDBR of different durations. The very One possible confounding variable has involved the is-
short-term adaptation during the first hours is characterized sue of identifying the effects of HDBR per se from those
by an increase in atrial natriuretic peptide (ANP) and a induced by confinement. Two studies (level of activity not
decrease in plasma renin activity (PRA) (Maillet et al. known) compared the hormonal changes induced by con-
1994). After 24 h, in response to the decrease in PV, PRA finement to those induced by HDBR: in a 4-day study in
increased, and remained high relative to aldosterone (with eight male volunteers, Sigaudo et al. (1996) showed that
dietary salt intake of 120 mEq/day) (Maillet et al. 1994; PRA increased and urinary ANP decreased in both situa-
Vernikos et al. 1993). Sodium excretion increased initially tions (confinement and HDBR). Plasma AVP decreased
and returned to basal values after 2–3 days. only after the 4-day confinement. Maillet et al. (1995)
Circulating levels of arginine vasopressin, cortisol and compared changes of blood regulating hormones during a
ACTH were unchanged after the first 24 h of HDBR. 4-week HDBR and a 4-week confinement. The renin-
A similar increase in PRA without change in aldosterone angiotensin-aldosterone system was enhanced under both
has been reported in longer bed rest studies. This was found conditions but AVP increased much more in confinement
in 14-day HDBR (–6) studies in male subjects on a high than in HDBR, probably due to the different hydration
salt diet (150 or 200 mEq/day) (Grenon et al. 2004a; status of the volunteers or as a manifestation of stress.
Schmedtje et al. 1996). A decrease in ANP and an increase However, confinement studies have not always controlled
in PRA were also reported during a simulation of a lunar for progressively reduced activity, with structured activity
mission both in –6 HDT and 10 HUT periods as well as a sessions and other encouragement to remain ambulatory
decrease in plasma volume by 11% (vs. sitting position) and active. Earlier studies that included groups of ambu-
(Pavy-Le Traon 1997a); the simulation of a lunar mission latory controls have shown progressive deconditioning in
was designed as follows: 4 days –6 HDT, 6 days +10 these subjects as well though not to the same extent as
HUT (to simulate lunar gravity, g/6, 4 days –6 HDT). This those in HDBR. Dissociating the role of posture change
study also showed an increase in the amplitude of circadian from inactivity in HDBR is not a simple matter.

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Fluid and salt intake are major issues in the assessment HDBR, with activation of the sympathetic nervous system,
of body fluid and hormone changes. Several investigators which subjects do not show during HDBR simulation
have tested the effects of various dietary sodium intake (Norsk 2005). These discrepancies raised the issue of the
levels on body fluid and hormonal regulation in HDBR. validity of the bed rest model and could reflect incomplete
Hinghofer-Szalkay et al. (2002a, b) studied plasma volume knowledge of the characteristics of each situation (Regnard
regulating hormones with high (HS-430 mmol/day) and et al. 2001). Norsk et al. (1998) and Norsk (2005) pointed
low (LS-140 mmol/day) sodium supply during an 8 day out the role of the transverse G-Stress (Gx) during ground
HDBR in ten men. ECV, assessed by body electrical simulations. He hypothesized that the total abolishment of
impedance spectroscopy, decreased with HDBR with a the G-stress in flight induces a more pronounced decrease
non-significant difference with altered salt intake (–4%, in intra-vascular volume than the decrease induced by the
LS; –5.8%, HS). Resting hormone levels were not altered HDBR, which results in stimulation of fluid retaining
by HDBR but aldosterone and AVP were lower with high mechanisms.
sodium intake than with low sodium intake. The authors
concluded that hormonal activities are more affected by Red cell mass
oral salt load than by HDBR. Recently, Williams et al.
(2003) carried out another study on this issue in 17 male A decline in red cell mass (RCM) becomes apparent after
volunteers. They hypothesized that increasing dietary so- approximately 2 weeks (Scianowski et al. 1995; review,
dium while controlling fluid intake would increase plasma Fortney et al. 1996). Fortney et al. (1994) reported a de-
osmolality, stimulate fluid conserving hormones and re- crease in RCM (expressed in ml/kg) after a 13-day HDBR,
duce fluid and electrolyte losses and that conversely similar in men and women. The decline in RCM continues
decreasing dietary sodium would have the opposite effects beyond 60 days of bed rest although at a slower rate
and increase fluid and electrolyte losses. They studied body (Kiselev et al. 1986; Lobachik et al. 1989; review, Fortney
fluid and regulating hormones before during and after a 21- et al 1996).
day (–6) HDBR with low [1 g (43 mmol)/day, LS], high Although decreased red cell mass has been observed
[10 g (430 mmol)/day, HS] or ‘‘usual’’ [4 g (174 mmol)/ consistently after bed rest, the etiology for the decline in
day] sodium intake. In HS, PRA, aldosterone, plasma RCM is not totally understood and most likely the result of
volume decreased, while ANP and AVP increased com- multiple factors; the inhibition of red cell formation seems
pared to controls; in LS, PRA, aldosterone, AVP increased to be a main factor (Talbot and Fisher 1986; review,
with no change in plasma volume compared to controls. Fortney et al. 1996). To study the mechanisms of the re-
The authors concluded that increasing dietary sodium duced red cell formation, changes in erythropoietin (EPO)
while controlling fluid intake during HDBR resulted in a levels have been measured by Gunga et al. (1996) under
greater loss of PV and that reducing dietary sodium did not several experimental conditions (bed rest, isolation and
alter the PV response compared to control subjects. confinement, and spaceflights). The main conclusions are
The mechanisms for the changes in renal excretory rates the following: HDBR causes a rapid decrease in EPO.
include a complex interaction of cardiovascular reflexes, Isolation and confinement induce also per se a reduced
neuroendocrine variables, and physical factors. Convertino EPO concentration. In short-term spaceflights, the astro-
et al. (2000) hypothesized that renal distal tubular cells nauts showed decreased or unchanged EPO concentrations.
may become less sensitive to aldosterone inducing a renal After a long-term spaceflight slightly elevated EPO was
capacity for sodium retention. To test it, they administered observed 24 h after recovery which increased markedly the
an acute bolus of aldosterone and measured renal responses following days. Branch et al. (1998) studied haematologi-
in monkeys during a 4-day 10 HDT but they found that cal responses to a 16-day HDBR. They reported a slight
renal response to aldosterone was not altered in this sim- decrease in RCM (–12%) with unchanged concentrations in
ulated microgravity model. EPO which may suggest a possible decrease in the
Some elements in the regulation of body fluid are sim- responsiveness of the erythropoeitic system.
ilar in HDBR and in flight like the decrease in plasma Erythrocyte metabolism and properties as well as some
volume, the dehydration of lower limbs and the decrease in haemorheological values have been studied in HDBR.
diuresis (Leach et al. 1996; Drummer et al. 2000a, b). Pawlak et al. (1998) reported some changes in enzymatic
Some differences between HDBR and spaceflight also antioxidative defence mechanisms and lipid peroxidation
exist. The renal responses to an isotonic saline infusion and in erythrocytes induced by long-term bed rest. Zezerov
an oral water load were attenuated during spaceflight et al. (1989, 1996) found that prolonged HDBR (120 days)
compared to that in ground based supine position but not in led to stimulation of lipid peroxidation measured as in-
HDBR (Norsk 1997; Norsk et al. 1998). Astronauts exhibit creased concentrations of lipid hydroperoxides and final
a fluid and sodium retaining state, less pronounced in products of lipid peroxidation in blood. Decreases in

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erythrocyte deformation and membrane fluidity in humans end-diastolic volume (LVDV) remained decreased after
and rabbits have been reported by Shen et al. (1997). The 1 week of spaceflight or HDBR (–8 to –13%) consistent
same investigators also reported a significant increase in with a moderate stable hypovolemia. The decrease in car-
abnormal erythrocyte, blood viscosity, haematocrit, diac size is due to reduced filling (hypovolemia), but in
fibrinogen, and red blood cell aggregation index in HDT addition cardiac atrophy may lead to reduced myocardial
rabbits. Ivanova et al. (1997a, b) reported shifts in the mass (Levine et al. 1997; Perhonen et al. 2001).
metabolic and structural parameters of erythrocytes ensu- To study whether the reduction in stroke volume (SV) is
ing degradation of the functional state of erythrocytes, i.e. due to specific adaptation of the heart to HDBR or to acute
changes in deformability and echinocytosis after prolonged hypovolemia alone, Perhonen et al. (2001) studied the left
bed rest and early recovery (120 days, female volunteers). ventricular-volume curves and Starling curves during
Scianowski et al. (1995) found a transient decrease in LBNP and saline loading in men before and after a 2-week
erythrocyte metabolic activity after 2 weeks of bed rest HDBR and after the acute administration of intra-venous
during a 30-day hypokinesia of patients with fractures of furosemide. Both HDBR and furosemide lead to a similar
the lower extremity. Reduced cell deformation, reduced reduction in plasma volume. SV was reduced more and the
plasma viscosity (as a result of diminished plasma proteins) Starling curve was steeper during orthostatic stress after
and enhanced red cell aggregation have been reported by HDBR. These investigators concluded that chronic HDBR
Lampe et al. (1992) after 9 days of HDBR. leads to ventricular remodelling which is not seen after
Although embolisms are clinically expected in bedrid- hypovolemia alone inducing a greater decrease in stroke
den patients, no evidence of similar incidents were ob- volume during orthostatic stress.
served in bed rested subjects. Clotting mechanisms have Several studies provided evidence that vasoconstriction
received almost no attention. However, platelet aggrega- during supine rest is increased and associated with hypo-
tion is known to increase with increases in Norepinephrine volemia (Convertino 2002a, b) if total peripheral resistance
and embolism formation may become a factor after bed rest is considered. Kamiya et al. (2004) showed that alpha-
and during rehabilitation. adrenergic responsiveness is unchanged after HDBR
(muscle sympathetic nerve activity measurements,
Blood pressure, heart rate, stroke volume MSNA). However, vascular adaptation probably differs in
and peripheral resistance the different vascular areas depending on haemodynamic
changes induced by the fluid shift. For example, by indirect
Effective maintenance of arterial blood pressure is depen- measurements by Doppler, Arbeille et al. (2001) reported a
dent on mechanisms that control heart rate, stroke volume, decrease in femoral arterial resistance but not in the cere-
and peripheral resistance. Resting blood pressure does not bral one with HDBR. Several studies in particular in ani-
vary significantly during HDBR. Shiraishi et al. (2003) mals (Wilkerson et al. 2005) support the hypothesis that
measured blood pressure variability in a 120-day HDBR microgravity-induced redistribution of transmural pres-
and found a tendency towards a decrease in the 24 h sures and flows across and within the arterial vasculature
amplitude of systolic blood pressure. may induce differential adaptations of vessels in different
Data on resting HR are few with no change or an in- anatomic regions (Zhang 2001).
crease depending on the bed rest duration. HR measure-
ments performed daily during a 90-day HDBR in males ECG changes
showed a progressive, increase in resting HR significant in
the second half of the study (ESA/CNES/NASDA clinical There are some anecdotal reports of ventricular arrhyth-
report). The 24 h ECG recordings performed in the same mias during spaceflight; however, it is not known whether
subjects showed a decrease in mean HR (compared to the spaceflight or microgravity systematically increases the
baseline period), due to the decrease in daily activity in risk of cardiac dysrhythmias (Convertino and Cooke 2005;
HDBR This was evident by the first recording (performed Sides et al. 2005). Few studies deal with electrical changes
after 15 days), with no further decrease as the HDBR in HDBR. Some T-wave changes have been reported on
progressed (Pavy-Le Traon et al. 2005). ECG responses measured from standard limb leads as
Subsequent experiments showed a decrease in cardiac mentioned in a review by Fortney et al. (1996) based on
size (echocardiographic and more recently MRI measure- past studies.
ments) with spaceflight and HDBR. Arbeille et al. (2001) Some ECG changes in bed rest could result from
summarised the results of the cardiovascular measurements changes in cardiac volume and in heart position. Increased
obtained by echocardiography and Doppler ultrasonogra- adrenergic stimulation may also favour rhythm disorders.
phy after various durations in space and in HDBR; the However, possible ECG changes with HDBR are not well
ejection fraction (EF) did not change, the left ventricular characterised and no clinically relevant ECG change has

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been reported. Recently Grenon et al. (2005) studied more obvious finding as indicated by a decrease in baroreflex
accurately cardiac repolarization; they looked at the sensitivity.
microvolt T wave alternans (MTWA) considered in pa- Impairment of the carotid-cardiac baroreflex response
tients as a predictor of sudden cardiac death, ventricular has been also reported in HDBR and in spaceflight by using
tachycardia, and ventricular fibrillation. They found an a neck chamber designed to change by suction and com-
increase in MTWA with HDBR, providing the first evi- pression the carotid arterial pressure and stimulate carotid
dence that simulated microgravity has a measurable effect sinus baroreceptors (Convertino 1991; Convertino et al.
on electrical repolarization processes. They also identified 1990; Eckberg et al. 1991; Eckberg and Fritsch 1992;
loss in potassium and changes in sympathetic function as Fritsch et al. 1992). Convertino et al. (1990) reported a
possible contributing factors. decrease in baroreflex gain with HDBR evident after
12 days and persistent up to 5 days after HDBR. Eckberg
Cardiovascular regulation by the autonomic and Fritsch (1992) also found a progressive decrease in
nervous system carotid-cardiac baroreflex gain during a 10-day HDBR. It is
more difficult to selectively study aortic baroreflexes.
The short-term regulation of blood pressure mainly de- Crandall et al. (1994) studied it in aortic baroreceptor-
pends on reflexes that involve the heart as well as the isolated conditions (phenylephrine + LBNP + neck pres-
peripheral vascular tone controlled by the autonomic ner- sure to offset the increased carotid sinus transmural pres-
vous system. Many studies have focused on the changes in sure). With this technique, they found an increase in the
the cardiovascular regulation by the autonomic nervous gain of aortic baroreflexes after 15 days of HDBR.
system using non-invasive HR recordings to assess heart Some investigators also looked at the ‘‘low pressure’’
rate variability (HRV) and sympathetic parasympathetic cardio-pulmonary baroreflexes. LBNP with a low pressure
balance. In a review, Fortrat et al. (1998, 2001) summar- level below 20 mmHg stimulates cardio-pulmonary
ised the results of cardiovascular variability in bed rest receptors, while –40 mmHg stimulates both low and high-
studies according to the bed rest duration. Most studies pressure baroreceptors. With this technique, Pannier et al.
reported a decrease in total HRV and in high frequency (1991) found that changes in vascular resistance with
power (HF) reflecting parasympathetic influence at rest. LBNP did not differ before and at the end of 24 h of HDBR
Some authors already reported these changes after 20 H (–5), but an exaggerated heart response was observed at –
(Wang et al. 1998b) and 4 days of HDBR (Pavy-Le Traon 40 mmHg level at the end of the HDBR. Convertino et al.
et al. 1997b). The decrease in HRV and in parasympathetic (1994a, b) found an increase in the sensitivity of the cardio-
indexes is evident in chronic adaptation to HDBR after pulmonary baroreflex control of forearm vascular resis-
2 weeks (Iwasaki et al. 2000), 4 weeks (Hughson et al. tance (LBNP: 0 to –20 mmHg) in 11 male volunteers after
1994, 1998), and 6 weeks (Pavy-Le Traon et al. 1998). The a 7-day HDBR.
same findings have been reported in spaceflight (Maillet Linnarson et al. (2006) showed an impairment during
et al. 1994; Goldberger et al. 1994a, b). Some investigators rapid posture changes at rest and exercise after a 120-day
looked more accurately at the complexity of cardiovascular HDBR.
dynamics. Hughson et al. (1994) using the coarse graining Therefore, reduced autonomic tone and heart rate
spectral analysis found a fractal alteration in HRV baroreflex has been repeatedly shown during HDBR, but
(assessing the ability of the system to integrate). But the effects of HDBR on the sympathetic nervous system
Golberger et al. (1994a, b) did not find any alteration in are still unclear.
cardiovascular complexity in HDBR and in spaceflight. As previously mentioned, urinary catecholamines de-
Changes in baroreflex gain have been studied both in creased in long duration HDBR. Data concerning sympa-
spaceflight and HDBR. The spontaneous baroreflex slope thetic indexes determined from HRV are more variable,
can be determined from spontaneous variability of BP with an increase or no change. Few studies are dealing with
interval and blood pressure by cross-spectral analysis the changes in total peripheral resistance (TPR) depending
(Robbe et al. 1987) or by a sequence method (Bertinieri on sympathetic stimulation, induced by baroreflex stimu-
et al. 1985; Yamamoto and Hughson 1991). Several lation. Xiao et al. (2002) developed a method to estimate
investigators have reported a decrease in spontaneous the static gains of both arterial and cardiopulmonary ba-
baroreflex slope during HDBR of different durations last- roreflexes from TPR and found a decrease in this static gain
ing from 4 to 42 days (Hughson et al. 1994; Pavy-Le Traon after a 16-day HDBR.
et al. 1998, 1998; Sigaudo et al. 1996, 1998; Iwasasaki Iwasaki et al. (2000) attempted to determine whether the
et al. 2000; Hirayanagi et al. 2004). changes of cardiac baroreflex regulation could be primarily
A decrease in the vagal control of the heart that favours due to hypovolemia. They studied in the same five male
greater sympathetic-parasympathetic balance, is the most subjects the effects of a 2-week HDBR, and of an acute

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hypovolemia (same decrease in PV) induced by furose- emia, Kimmerly and Shoemaker (2002) compared the
mide. They found no difference in cardiovascular indices effects of hypovolemia (diuretic administration) to nor-
such as cardiac filling pressures, blood pressure, stroke movolemia on neurovascular control during LBNP (–5 to –
volume and cardiac output. Normalised HF power (HRV 40 mmHg). They reported larger gains in %delta MSNA/
assessment), reflecting parasympathetic influence de- delta central venous pressure and %delta TPR/delta central
creased in both conditions as well as the index of arterial- venous pressure in favour of an increased neurovascular
cardiac baroreflex sensitivity. However, the low frequency component of BP in hypovolemia.
power of BP variability (mainly under sympathetic influ-
ence) increased largely with furosemide and decreased Orthostatic intolerance
with HDBR. These results show that changes in cardiac
baroreflex control are largely related to the decrease in PV 0rthostatic intolerance (OI) is observed even after short-
but also suggest changes in vasomotor responses with term HDBR (Arbeille et al. 1998; Convertino et al. 1990;
HDBR. Pavy-Le Traon et al. 1997b). Several tests have been used
Different tests have been performed to evaluate the to assess orthostatic tolerance: stand test, without or with
ability of the cardiovascular system to adapt by studying the back leaning on a wall-head up tilt test (from +60 to
parasympathetic/sympathetic activation including ortho- +80 and various durations, 10 to 20 min, up to 60 min in
static stress. New insights on the sympathetic system were some studies), LBNP with defined level of negative pres-
more recently provided by experiments with muscle sym- sure (in general maximum level of –40 or –50 mmHg) and
pathetic nerve activity (MSNA) measurements performed time of exposure, or until presyncope onset. Centrifugation
at rest and during autonomic activation. Spaak et al. (2001) has been used as well as a means of evaluating the severity
studied the BP and HR response to a sustained hand grip of cardiovascular de-conditioning resulting from bed rest.
(30% maximum contraction force for 2 min), before, dur- This is accomplished by comparing the tolerance to cen-
ing and after 120 days HDBR in six subjects and found a trifugation-induced Gz acceleration (to relatively high G
reduced BP and HR response the first days of HDBR. They levels; often around 3 G) before and after the experiment
also found a reduced BP response in four astronauts within (Vil-Villiams and Kotovskaya 1994).
1–4 days after their return of a long duration flight (179 Many bed rest studies have focused on mechanisms of
and 389 days). Sympathetic vasomotor reactivity can also orthostatic hypotension and comparison of physiological
be studied during a cold pressor test. Haruna et al. (1994) functions in tolerant and intolerant subjects in order to
did not find any change in BP changes during a cold identity possible physiological markers of ‘‘susceptibil-
pressor test after a 20-day horizontal bed rest in six healthy ity’’ to OI (Ludwig and Convertino 1994; Pavy-Le Traon
volunteers (five men and one woman). et al. 1999; Meck et al. 2004; Blaber et al. 2004; Grenon
Kamiya et al. (1999a, b, c) showed an increase in resting et al. 2004b) Over many years, different causes of OI
vasomotor sympathetic tone (MSNA tibial nerve) with have been identified: hypovolemia, hormonal and meta-
long-term HDBR (60 and 120 days) with no change in BP. bolic changes, increase in venous distensibility, changes
The same team (Kamiya et al. 2000) studied the effects of a in cardiovascular regulation by the autonomic nervous
14-day –6 HDBR on vasomotor sympathetic and periph- system, and so on. The inability to adequately elevate
eral vasodilator responses to mental arithmetic stress. They peripheral resistance and possibly the altered autoregu-
found an increase of total MSNA more pronounced after lation of cerebral vasculature during spaceflight or
HDBR than before, but the decrease in calf vascular HDBR are considered as important factors in post-flight
resistance (measured by dividing mean blood pressure by (or post bed rest) orthostatic intolerance (Convertino
calf blood flow) before HDBR during mental stress was 2002a, b; Zhang 2001).
abolished after HDBR. Changes in blood pressure and
heart rate did not differ before and after HDBR. The au- Mechanisms involved in orthostatic intolerance
thors suggest increased vasomotor sympatho-excitation but
attenuated vasodilatation in the calf muscle. The same Hypovolemia and changes of volume regulating hormones
investigators also measured MSNA during a 60 HUT have been previously discussed and are summarised in
before and after a 120-day HDBR in six male volunteers. Figs. 2 and 3.
Resting supine MSNA was greater, the increase in MSNA Changes in autonomic cardiovascular regulation are one
during HUT did not differ before and after HDBR, but of the main factors of OI. The reduced carotid-cardiac
mean BP decreased and the BP interval reflex control was baroreflex sensitivity may impair the capacity of elevation
flatter after HDBR. in heart rate and subsequently cardiac output during
To investigate further the mechanisms of the cardio- standing (Convertino 2002a, b). Changes in cardiac baro-
vascular regulation during orthostatic stress in hypovol- reflex control are largely related to the decrease in PV

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(Iwasaki et al. 2000, 2004). However, impaired carotid- MSNA/pulmonary capillary wedge pressure relationship
cardiac baroreflex function and hypovolemia are probably was unchanged suggesting a shift on the stimulus-response
additive factors of OI (Convertino 2002a, b; Convertino curve due to hypovolemia. The authors also reported that
et al. 1990). the relationship between limb vascular resistance and
The most important fact is the inability to adequately MSNA was not significantly altered and concluded that bed
elevate peripheral resistance. Therefore, recent studies have rest does not alter reflex control of MSNA. In contrast,
focused on sympathetic activation. Most of the different Khan et al. (2002) reported reduced sympathetic nerve re-
studies using MSNA showed an increase in MSNA at rest sponses (MSNA) during graded LBNP but this study was
and/or a greater MSNA response during sympathetic stim- performed after a shorter (24 h) HDBR and with high
ulation including orthostatic stress in HDBR studies (14,18, LBNP levels (until presyncope or –60 mmHg).
60 and 120 days). As previously discussed, the increase in However, MSNA differed according to the orthostatic
MSNA during orthostatic stress is probably due to hypo- tolerance of the volunteers at the end of the HDBR. Ka-
volemia. To determine whether changes in autonomic miya et al. (2003) examined MSNA during a 15-min 60
function might produce orthostatic intolerance, Pawelczyk HUT before and after a 14-day HDBR in 22 subjects. Ten
et al. (2001) studied stimulus-response curves relating limb subjects demonstrated orthostatic intolerance. In these
vascular resistance, MSNA, and pulmonary capillary wedge subjects, MSNA increased with posture during several
pressure in seven subjects before and after an 18 day minutes of HUT but was suppressed by 104% from the
HDBR. LBNP and rapid saline infusion were used to pro- resting supine level the last minute of HUT, accompanied
duce changes in pulmonary capillary wedge pressure. by a drop in BP. In contrast, activation of MSNA was
Orthostatic tolerance was assessed by graded LBNP until preserved in tolerant subjects. These results support the
presyncope. During LBNP, pulmonary capillary wedge thesis of reduced sympathetic activity in subjects with
pressure was lower and MSNA greater after HDBR but the orthostatic hypotension.

SPACE ENVIRONMENT
WEIGHTLESSNESS
Immediate Delayed
Loss of Hydrostatic Gradient
(< 24 h) (> 24 h)
Inactivity ?

Change in body fluid Adaptation to Muscle

distribution Hypovolemia and Atrophy
Sodium Loss

Central Blood Volume Potassium

Loss
Pre-load
Stroke Volume
Central Nervous System
ANF Altered Adrenergic
Baroreceptor Response
Thirst Response

GFR
Sympathetic ( ?) AVP
AVP Nervous System ANF
Cardiac Volume
Activity Renin
Angiotensin II
Aldosterone
Altered Receptor Thirst
Insensible Responses ?
Renin Water Loss ?
Angiotensin II
Aldosterone ?

Water
Reabsorption Altered
Circadian
Urine Flow Vascular Rhythms
Natriuresis T o ne Plasma Volume
RCM
Body Sodium ?
O t he r
Factors ?
Orthostatic Hypotension

Fig. 3 Suggested cardiovascular responses to real and simulated rhythms remain unclear. Changes in AVP in HDBR are variable (see
weightlessness (from Gharib and Hughson 1992). Most of them have corresponding text). Mechanisms of the decrease in red cell mass
been confirmed in HDBR experiments. Inactivity certainly plays a (RCM) are discussed in the text. ANF atrial natriuretic factor, AVP
role in the cardiovascular deconditioning onset. Changes in circadian arginine vasopressin, GFR glomerular filtration rate

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Eur J Appl Physiol (2007) 101:143–194 155

Different hypotheses have been proposed to explain the terised by acute changes in arterial blood pressure and flow,
reduced vasoconstrictive responses in intolerant subjects. which modify wall shear stress, the major physiological
Convertino (1999, 2002a, b) suggests that as maximal stimulus to the endothelium. Bonnin et al. (2001) investi-
vasoconstriction is finite, the elevated resting vasocon- gated the flow-dependant dilatation (post ischemic hyper-
striction associated with low circulating and stroke vol- emia following occlusion) and flow-independent dilatation
umes represents a reduction in vasoconstriction reserve and (administration of glyceryl trinitrate) in the brachial artery
lowers the capacity to buffer orthostatic hypotension. before and at the end of a 7-day (–6) HDBR. They found
Changes in adrenergic receptors may also contribute. an enhanced flow-dependant vasodilatation which may
Chronic reduction in catecholamine levels leads to super- contribute to orthostatic intolerance since the vasodilata-
sensitization of beta-adrenergic receptors when they are tion was negatively correlated to the post-bed rest duration
stimulated on isolated target cells or in vivo during iso- of the stand test. No change was observed with HDBR
proterenol or epinephrine infusion (Convertino et al. during the administration of glyceryl trinitrate, an exoge-
1997a; Barbe et al. 1998, 1999). Increased beta vaso-dil- nous nitric oxide (NO) donor. The contribution of NO to
atory response could limit vasoconstriction. However, orthostatic intolerance is still unclear. Given the potent
vasoconstriction depends mainly on alpha-adrenergic vasodilatory and natriuretic functions of NO, Vaziri et al.
receptors. Few studies deal with changes of alpha-adren- (2000) hypothesized that cardiovascular adaptation to
ergic receptors. Indirect assessment of their response by microgravity may involve an up-regulation of the NO
measuring the transduction gain from total MSNA into calf system. The results of their experiments suggest enhanced
vascular resistance showed that alpha-adrenergic vascular i-NOS (inducible NO synthase) generation in hindlimb
responsiveness to sympathetic nerve activity is preserved unloaded rats (20 days).
in the supine position after a 14-day –6 HDBR (Kamiya The same team showed different responses according to
et al. 2004). the vascular area which indicate that the endothelial
Maass et al. (1992) looked at the densities of alpha 2- vasodilator mechanisms may be up-regulated in the carotid
receptors on platelets, beta 2-receptors on lymphocytes, artery, whereas the inducible NOS expression/activity may
and the responsiveness of beta 2-receptors to isoproterenol be increased in the femoral artery from HU rats (Sangha
stimulation before and after a 10-day HDBR. The densities et al. 2000).
of alpha 2- and beta 2-receptors were low before HDBR, As mentioned by Convertino (2002a, b), there is also
and were high during HDBR. While the density of alpha 2- evidence from ground based animal studies that morpho-
receptors decreased after HDBR that of beta 2-receptors logical vascular and/or perivascular innervation changes as
remained high. The increase in receptors density may be a result of exposure to simulated microgravity. Experiments
explained by an up regulation in accordance with the de- performed by Delp et al. (2000) indicate that structural
crease in catecholamines during the HDBR. In contrast remodelling and functional adaptations of the arterial
with other studies, no changes in the responsiveness of beta microvasculature occur in skeletal muscles of the HU rat;
2-receptors were observed. The authors also suggested a the data suggest that these alterations may be induced by
possible down-regulation of the receptors before HDBR in reductions in transmural pressure and wall shear stress.
response to a stressful situation. There were no changes in The same team and other investigators studied in par-
receptor characteristics specifically attributable to HDBR. ticular the cerebral vasculature. In hind limb unloaded rats
One of the hypotheses to explain reduced sympathetic (2 weeks), Wilkerson et al. (1999) found an increase in the
vasomotor activity is altered central nervous control. Some media cross-sectional area and thickness of cerebral basilar
data are provided by studies in animals, in particular using artery while there was no significant change in mesenteric
the hindlimb unloaded rat model. In a review, Hasser and or splenic resistance artery morphology. They suggest that
Moffitt (2001) summarised some main results; these studies hindlimb unloading-induced increases in cephalic arterial
on rats showed a blunted baro-reflex mediated activation of pressure and, correspondingly, increases in circumferential
both renal and lumbar sympathetic nerve activity in re- wall stress resulting in the hypertrophy of basilar artery
sponse to a hypotensive stimulus. Baroreceptor afferent smooth muscle cells.
activity in response to changes in BP is unaltered in these More recent studies performed by the same team on the
rats but increases in efferent sympathetic activity are middle cerebral arteries (MCA) indicate that chronic ce-
blunted which suggests an altered central nervous system phalic fluid shifts enhanced basal tone and vasoconstriction
control. This might be related to an enhancement of the through alterations in the eNOS signalling mechanism
GABA-mediated inhibition in the rostral ventrolateral (Wilkerson et al. 2005). The potential functional conse-
medulla. quence of these vascular alterations with HDT is regional
The endothelium is also considered a key factor in the elevation in cerebro-vascular resistance (CVR) and corre-
regulation of vasomotor tone. Orthostatic stress is charac- sponding reductions in cerebral perfusion.

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The influence of bed rest on cerebral arteries and cere- find a relationship between reduced leg venous compliance
bral haemodynamics in humans is not clear. Cerebral and tolerance to LBNP after an 18 day HDBR. It appears
haemodynamics have been indirectly studied using trans- that excessive blood pooling in the legs is a contributory
cranial Doppler. Sun et al. (2005) reported a persisting but not a main factor in post bed rest orthostatic intolerance
decrease in MCA mean blood flow velocity (BFV) during a and possibly depends on bed rest duration. The excessive
21-day HDBR. After an initial increase during the first blood pooling in the legs is certainly favoured by muscular
hours, Kawai et al. (1993) also reported reduced values of atrophy in particular in long duration bed rest studies, but
MCA BFV after 6 h of –6 HDBR. Zhang et al. (1997) even if less innervated than arteries, an impaired vein
studied MCA cerebral blood flow velocity during graded constriction could also contribute to OI.
LBNP before and at the end of a 2-week –6 HDBR. Neuro-vestibular changes with HBBR are not well
Compared to pre-bed rest, post-bed rest mean velocity was known. Some studies have demonstrated that signals from
lower by 11,10 and 21% at –30, –40 and –50 mmHg vestibular organs play an important role in regulating BP
respectively with no difference at maximal LBNP. The during changes in posture in a one G environment (Yates
authors concluded that there was an impaired cerebral au- and Kerman 1998). It has been shown that vestibular
toregulation evidenced by this earlier and greater fall in stimulation associated with head movements in yaw
cerebral blood flow velocity during LBNP. Arbeille et al. inhibits vagally mediated baroreflex control of heart rate
(1998) also investigated the cerebral and femoral blood (Convertino et al. 1997b). Even if the vestibular changes
flow by Doppler during HUT (70 30 min) and LBNP (–20 are not comparable with those reported in flight, the role of
to –50 mmHg) before and after a 4-day HDBR. They did vestibular dysfunction and vestibular-cardiovascular inter-
not find significant differences in cerebral haemodynamic actions in the onset of orthostatic intolerance after HDBR
responses before and after HDBR, while in contrast, fem- should be considered.
oral blood flow was reduced less and femoral resistance
index increased less after HDBR. These changes in femoral Predisposing factors
responses were pronounced in intolerant subjects. No sig-
nificant impairment of cerebral autoregulation was reported Several studies tried to identify factors which differentiate
during the drop in blood pressure (BP) induced by quickly tolerant from intolerant individuals. This has been done by
deflating thigh cuff after a 4-min arterial occlusion (tech- comparing cardiovascular responses induced by bed rest in
nique initially described by Aaslid et al. 1989) after 5 days the two groups, in particular cardiovascular responses to
of –6 HDBR in eight healthy women (Pavy-Le Traon orthostatic stress. The objective of some studies was also to
et al. 2002). This thigh cuff manoeuvre assesses a very fast point out predisposing pre-flight (or pre bed rest) indicators
acting mechanism. However, the time to maximum de- of post-flight (or post bed rest) orthostatic intolerance (OI).
crease in cerebro-vascular resistance index (expressed as Some interesting data are provided by spaceflight stud-
the ratio of mean BP to mean MCA velocity) was larger in ies. After short duration flights approximately 20% of the
the five women who presented orthostatic intolerance astronauts experience presyncope during upright position
suggesting that some differences in cerebral autoregulatory on landing day. Low vascular resistance before and after
responses could contribute to the OI. flight and low norepinephrine release during orthostatic
Nevertheless, even if suitable for assessing rapid chan- stress on landing day have been found in intolerant astro-
ges in cerebral blood flow and dynamic cerebral autore- nauts. Meck et al. (2004) looked more accurately at the
gulation, TCD measurements have limitations. Absolute mechanisms in particular at sympathetic function and cat-
CBF and intracranial pressure were not measured. echolamine metabolism in 29 astronauts. Their results
Changes in venous properties are another factor. Several suggest low alpha-adrenergic responsiveness before flight
HDBR studies have shown an increase in venous disten- and changes in central nervous system control such as
sibility (decrease in compliance) as determined by venous sympathetic responses to baroreceptor input become im-
occlusion plethysmography (Louisy et al. 1995a, b, 1997; paired. To our knowledge, a similar complete investigation
Blecker 2004). During a 6-week HDBR, Louisy et al. has not been performed in HDBR with a sufficient number
(1997) observed the maximum increase in distensibility of individuals. Blaber et al. (2004) used heart rate vari-
after 4 weeks. But the contribution of altered venous ability (HRV) to determine whether autonomic regulation
compliance to the orthostatic intolerance is not clear. Some of the heart in the same 29 astronauts who did or did not
studies report a possible role of increased lower limb ve- experience post-flight orthostatic intolerance was different
nous distensibility in orthostatic intolerance after HDBR of pre-flight and/or was differentially affected by short dura-
various durations (4, 14, 28, 30 and 42 days) (Pavy-Le tion (8–16 days) spaceflight. Finishers and non-finishers
Traon et al. 1999) and after 90 days of HDBR (Belin de had an increase in sympathetic activity with stand on pre-
Chantemerle et al. 2004b). Blecker et al. (2004) did not flight, yet only finishers retained this response on landing

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day. Non-finishers also had lower sympathovagal balance only astronaut health issue for which a large enough data
and higher pre-flight supine parasympathetic activity than set exists to allow valid conclusions to be drawn about
finishers. These results suggest pre-flight autonomic status gender differences is orthostatic intolerance following
and post-flight impairment in autonomic control of the shuttle missions, in which women have a significantly
heart may contribute to orthostatic intolerance. higher incidence of presyncope during stand tests than do
In HDBR, several studies showed a reduced vasomotor men.
response during orthostatic stress in intolerant subjects. Two experiments have compared cardiovascular and
The different factors of susceptibility to OI, as previously endocrine responses induced by a 7-day –6 HDBR in eight
described, are generally studied by different scientific men and eight women and reported only slight gender
teams. In the case of countermeasure effectiveness, com- differences (Vernikos et al. 1993; Millet et al. 2001).
parison of control and countermeasure groups also provide Vernikos et al. (1993) reported no gender differences in the
information on the factors involved in OI depending on the endocrine responses (RAAS, AVP) except for cortisol and
way the countermeasure acts. However, few studies looked ACTH. Urinary cortisol increased and remained elevated
at several, already well known, or potential contributory throughout the HDBR in males only. The ratio of early
factors to OI at the same time. This is probably due to the morning ACTH to cortisol was lower in females than in
small number of volunteers in each study, compared to the males because ACTH was lower in females. There were
number of potential factors to be studied. Grenon et al. also significant sex differences in cardiovascular responses
(2004b) performed HUT tests before and after a 14–16 day to standing before and after HDBR. Females had greater
HDBR in 24 male volunteers to identify individual pre- PRA and Aldo responses to standing before HDBR and
disposition. Even in the pre-HDBR test, a high percentage larger Aldo responses to standing after HDBR. Millet et al.
of individuals showed OI (11/24); these subjects had lower (2001) reported a similar decrease in PV in both men
serum aldosterone, lower leg venous compliance, higher (9.1 ± 1.4%) and women (9.4 ± 0.8%). The hormonal re-
supine parasympathetic responsiveness and lower standing sponses (decrease in urinary normetanephrine; increase in
sympathetic responsiveness. Of the 14 subjects who com- plasma active renin (AR) and aldosterone) were compara-
pleted the post HDBR head up tilt test, nine had surpris- ble. The results showed similar cardiovascular and endo-
ingly been intolerant before the HDBR. Intolerant subjects crine responses to standing after HDBR. However, the
also had lower baseline cortisol and higher sodium levels. orthostatic intolerance following HDBR was associated
This study points out some predisposing factors, like higher with a blunted increase in noradrenaline (NA) during the
supine parasympathetic activity, also identified in space- stand test only in the women. In the same experiment,
flight. However these data raise the issue of the reproduc- Custaud et al. (2002) looked at the cardiac baroreflex; the
ibility of the orthostatic test, since nine among the 14 decrease in spontaneous baroreflex sensitivity did not differ
subjects who completed the post HDBR test were intoler- in men and women. Only some changes in diastolic blood
ant before. pressure were observed at the highest level of LBNP after
Pavy-Le Traon et al. (1999) looked at different factors HDBR characterised by an increase in men and a small
which might contribute to OI in 47 healthy men who par- decrease in women suggesting impaired vasoconstriction in
ticipated in –6 HDBR of various durations (4, 14, 28, 30 women.
and 42 days) with or without different countermeasures Some research has been performed to assess the differ-
(LBNP, LBNP + exercise (performed separately), medical ences with gender during postural stress and sympathetic
stockings). The following factors were studied: individual stimulation. Shoemaker et al. (2002) reported smaller
physiological and physical factors (basal supine ABP, increments in muscle sympathetic nerve activity (MSNA)
height), physiological changes induced by exposure to in healthy women during graded HUT and a non-baroreflex
HDBR (decrease in PV, increase in venous distensibility), cold pressor test. Ludwig et al. (2001) suggest that the
HDBR duration and countermeasure application. Nineteen distribution of adrenergic receptor sites differ with gender.
out of 47 subjects showed OI after HDBR. The occurrence Women may have a higher density of receptor sites in the
of OI was associated with greater height, low resting BP, arterioles (fast acting with low gain) while men may have
greater changes in resting lower limb distensibility, and higher density in the larger vessels (slow acting with high
absence of countermeasures. Low resting BP was already gain). Studies in animals performed in hind limb unloaded
reported as a predisposing factor in spaceflight. The influ- rats showed that both female gender and hind limb
ence of height as a predisposing factor of OI has been unloading attenuated baroreflex mediated increases in
reported as well by Ludwig and Convertino (1994). sympathetic activity (Foley et al. 2005).
Female gender seems to be one of the predisposing The influence of physical training on orthostatic intol-
factors (Waters et al. 2002). In a review on gender issues erance has been debated for years. Many reports support
related to spaceflight, Harm et al. (2001) concluded that the the idea that chronic endurance exercise training reduces

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orthostatic tolerance, mainly based on the comparison of 7.3% in the men and women, respectively. The reductions
unfit subjects and endurance athletes. In a review on this in peak VO2 were comparable to the reductions of 9.3 and
topic, Raven (1993) and Raven and Pawelczyk (1993) re- 7.8% observed in earlier studies with young men
port that exercise training, rather than VO2max reduces (21 ± 1 years) and women (28 ± 2 years).
orthostatic tolerance. They identified at least four factors In a review, Convertino (1997) and Convertino et al.
associated with exercise training that contribute to the (1997c) summarise the physiological mechanisms of the
development of orthostatic intolerance: (a) increased limb reduced maximal oxygen uptake: VO2max is reduced pri-
compliance, (b) eccentric ventricular hypertrophy, (c) in- marily because of decreased maximal stroke volume and
creases in total blood volume, which may attenuate car- cardiac output, primarily the result of decreased venous
diopulmonary baroreflex responsiveness, shift ventricular return associated with lower circulating blood volume.
function to a steeper portion of the ventricular compliance VO2max, stroke volume, and cardiac output are further
curve, and increase the inhibitory effect of cardiopulmo- compromised by exercise in the upright posture. Reduction
nary baroreceptors on carotid baroreflex responsiveness; in baseline and maximal muscle blood flow, red blood cell
and (d) an independent effect that reduces carotid and volume, and capillarization in working muscles represent
aortic baroreflex responsiveness. peripheral mechanisms that may contribute to limited
In contrast, Mtinangi and Hainsworth (1999) showed oxygen delivery and, subsequently, lowered VO2max. Thus,
that moderate exercise training increases orthostatic toler- alterations in cardiac and vascular functions induced by
ance in subjects who do not already have a high initial prolonged confinement to bed rest contribute to diminution
tolerance and suggest that training may be of value in the of maximal oxygen uptake and reserve capacity to perform
management of untrained patients with orthostatic intol- physical work.
erance. By data obtained from measurements of VO2, Qc, stroke
Based on these different findings some investigators volume, arterial O2 saturation, blood haemoglobin con-
have developed models aiming to predict the susceptibility centration, arterial O2 concentration, and QaO2 during a
to OI based on physiological measurements (Ludwig and 100-W exercise, Ferretti et al. (1998, 2002) suggest that the
Convertino 1994; Grenon et al. 2004b). Because of large O2 transport system is down-regulated after a 42-day
inter-individual variability and different conditions of HDBR. The same investigators (Ferretti et al. 1997) by
spaceflight and HDBR, this kind of model will necessitate studying the cardiovascular and muscle changes concluded
simple non-invasive measurements and a great number of that interaction between these muscular and cardiovascular
subjects (including astronauts) to be validated. effects led to a smaller reduction in VO2max than in car-
diovascular O2 transport. Yet the latter appears to play the
Decrease in exercise capacity greatest role in limiting VO2max after bed rest (>70% of
overall limitation), the remaining fraction being shared
Reduction of exercise capacity with bed rest is well rec- between peripheral O2 diffusion and utilization.
ognized (Convertino 1993, 1997; Convertino et al. 1986, Impaired thermoregulatory responses have been ob-
1997c; Ferretti et al. 1997, 1998, 2002; Greenleaf 1997; served during exercise and passive heating after HDBR
Greenleaf et al. 1989, 1992; Machinskii et al. 1987). A exposure (Lee et al. 2002; Crandall et al. 2003; Shibasaki
reduction of 31% peak aerobic exercise capacity (VO2 et al. 2003). In particular, cutaneous vasodilation and sweat
peak) has been reported after 30 days of HDBR (Greenleaf rate were reduced during a thermal challenge after simu-
et al. 1989, 1997). After a 42-day HDBR, Ferretti et al. lated and actual microgravity exposure (Crandall et al.
(1997) found a decrease of 16.6% in peak VO2; the con- 2003). This team studied maximal forearm cutaneous
comitant decreases in Qmax (–30.8%), essentially due to a vascular conductance (plethysmography) and sweat gland
change in stroke volume, and in Hb led to a huge decrease function (acetylcholine intradermal microdialysis) during a
in O2 delivery (–39.7%). The magnitude of reduction in 14-day HDBR. Lee et al. (2002) suggest a centrally med-
VO2max is dependent on the duration of bed rest and the iated elevation in the thermoregulatory set point during bed
initial level of aerobic fitness (VO2max), but it appears to be rest exposure.
independent of age or gender (Convertino 1997; Conver-
tino et al. 1986, 1997c). Convertino et al. (1986) compared Pulmonary function
the effects of age and gender on aerobic capacity following
10 days of BR. In middle-aged men (55 ± 2 years) and Few studies deal with pulmonary function in HDBR. In a
women (55 ± 1 years), peak VO2 decreased significantly review, Fortney et al. (1996) summarised the adaptation
from 35.6 to 32.6 ml kg–1 min–1 (–8.4%) in the men and processes induced by bed rest: when a person moves to
from 26.5 to 24.7 ml kg–1 min–1 (–6.8%) in the women, supine position, decreased lung volume and increased air-
while total exercise tolerance time was reduced by 8.1 and way resistance resulting from increases in intra-thoracic

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and pulmonary blood volumes and direct compression of negative impact of HDBR was noted on the ability to
airways by blood volume may affect pulmonary function; acclimatize to hypoxia in terms of pulmonary mechanics,
on the other hand, some positive effects include decreased gas exchange, circulatory or mental function measure-
physiological dead space, improved ventilation-perfusion ments. Arterial blood gases and oxygenation were not
matching and lung diffusion capacity. seriously affected by simulated microgravity.
Pulmonary function (forced vital capacity and total lung
capacity measured by helium dilution) was assessed in Countermeasures
supine subjects before, during, and after three separate bed
rest studies of 11 and 12 days duration by Beckett et al. Fluid and salt loading
(1986). They found a small significant increase in forced
vital capacity and in total lung capacity (TLC) while Astronauts are used to taking a maximum of 8 g of salt
residual volume and functional residual capacity of the with nearly 1 l of water 2 h before re-entry. As shown by
respiratory system did not change. Bungo et al. (1985), this salt and water loading induces a
Several Chinese investigators pointed out some cardio- transient increase in PV and reduces the orthostatic
pulmonary changes with HDBR, in particular in the early tachycardia after short duration flights. Attempts to restore
days. Changes of cardiopulmonary circulation during 7 day PV with isotonic fluid drinking or infusion in HDBR have
HDBR were studied by Wang et al. (1998b, 1999). The failed (Vernikos and Convertino 1994). There is some
results showed that increased pulmonary arterial pressure, evidence that the operating range for the sensing mecha-
increased preload of left and right heart, increased right nisms of vascular volume may be reset to a lower adap-
myocardial contractility and congestion of the lungs ap- tation after microgravity (Convertino 1996, 2002a, b). Heer
peared during 24 h bed rest, after which right myocardial and Gaffney et al. (1992) showed that a rapid infusion
contractility decreased. Wei et al. (2003) investigated the (22 ml/kg over 20 min) of isotonic saline before, during,
effects of a 21-day HDBR on pulmonary gas distribution and after a 10-day HDBR [under strictly controlled water
and little airway function. They concluded that indices of intake (40 ml/kg) and sodium intake (2.2 mmol/kg)] pro-
pulmonary gas distribution were affected and pulmonary duced a transient blood volume expansion with 18% of the
gas distribution was more uneven during and after HDBR. infusate retained intravascularly after 2 h. HDBR did not
Lu et al. (2000) investigated the effects of acute simulated alter the magnitude and the time course of the cardiovas-
weightlessness by a 45-min –30 HDT on lung function. cular responses induced by the infusion (Drummer et al.
Their data suggest a decrease of pulmonary ventilation and 1992; Heer et al. 1992; Gaffney et al. 1992). In contrast,
lung capacity. They found a dramatic increase in pulmo- Bestle et al. (2001) showed that the natriuretic response to
nary diffusion which might be related to uniform distri- an isotonic saline infusion was augmented after one week
bution of pulmonary blood flow and increased effective of –6 HDBR, whereas the response to hypertonic saline
pulmonary vascular bed perfusion. was unaltered. Therefore, these data seem controversial
More recently, Montmerle et al. (2002) determined the and recently Waters et al. (2005) showed that fluid loading
effects of a 120-day HDBR on lung mechanics and gas (salt tablets and water) at the end of a 12-day HDBR re-
exchange. Peak expiratory flow did not change. The data stored plasma volume and resulted in the absence of post
did not support major respiratory muscle deconditioning bed rest orthostatic hypotension and changes in supine
after 120 days of HDBR. The decrease in maximal haemodynamic and endocrine variables. However in this
midexpiratory flow suggests a reduction in elastic recoil. study, despite normovolemia, beta adrenoreceptors were
Time courses of volume-corrected DL (CO) (diffusing up-regulated and HR, epinephrine and PRA responses to
capacity for carbon monoxide corrected to a standardized tilt test were augmented.
alveolar volume) and pulmonary blood flow could be ex-
plained by a decrease in central blood volume during and Lower body negative pressure
immediately after HDT.
Vil-Viliams and Kotovskaya (1994) studied external Lower body negative pressure (LBNP) induces a fluid shift
respiration changes during exposure to +Gx acceleration from the upper to the lower part of the body. The subject’s
after simulated and real microgravity of varying duration legs are enclosed in a chamber or trousers (below the iliac
and conclude that these changes are extremely small. crests) and exposed to negative pressure. Levels of about –
To determine the effects of hypoxia on physiological 40 to –50 mmHg are considered to produce, in supine
responses to simulated zero-gravity, cardiopulmonary and subjects, blood shifts very similar to those induced by the
fluid balance measurements were made in six subjects upright posture. LBNP has been developed to assess car-
(acclimatized to 5,400 ft) before and during 5 HDBR over diovascular responses to orthostatic stress, and is com-
8 days at 10,678 ft (Loeppky et al. 1993). No significant monly used in-flight and during HDBR experiments. LBNP

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is also used as a countermeasure to prevent the orthostatic ments have confirmed the advantage of combining LBNP
arterial hypotension encountered after spaceflight and with other countermeasures, in particular muscular exer-
HDBR. cise. As a result, during the past few years, US scientists,
Russian scientists have the greatest experience in this including investigators from NASA Ames Research
field in flight. LBNP tests were performed using a ‘‘Chibis’’ Center, have been testing the effects of muscular exercise
suit (trousers) to assess orthostatic tolerance and to evalu- in conjunction with LBNP sessions during bed rest
ate the effects of countermeasures generally every other experiments. LBNP combined with treadmill exercise in
month. LBNP has also been used as a countermeasure supine subjects provides both cardiovascular and musculo-
during the last month of long-term spaceflight in associa- skeletal stimulation. First, Murthy et al. (1994) compared
tion with other countermeasures like fluid loading (intake exercise (5 min in duration) in a supine position within an
of water and salt tablets during the last days of the flight) LBNP chamber (–100 mmHg) to 5-min of exercise in the
and regular muscular exercise (performed throughout the upright position and concluded that this combination of
flight). The pre-landing training sessions began 16 to exercise and LBNP produces the same musculoskeletal
20 days before landing and consisted of a 20-min session stress in the legs and greater cardiovascular stress than
every 4 days and of two sessions lasting nearly 1 h each exercise in the upright position. Lee et al. (1997a, b)
the last 2 days before landing (Gazenko and Kasyan 1991). showed that 30-min bouts of intense interval upright
As reported by Russian scientists, these LBNP sessions exercise training or supine exercise (treadmill) training
in association with the other countermeasures have bene- against LBNP (–52 mmHg) followed by 5 min of static
ficial effects on orthostatic tolerance (Kozlovskaya et al. LBNP is sufficient to maintain upright exercise training
1995). LBNP in combination with fluid loading is believed after 5 days of bed rest. Watenpaugh et al. (2000) also
to act by promoting a transient positive fluid balance reported beneficial effects on exercise performance
resulting in an increase in vascular, as well as extra-vas- resulting from 40 min of supine exercise per day in a
cular fluid. LBNP also may provide beneficial orthostatic LBNP chamber (–52 mmHg) during a 15-day HDBR
effects by restoring baroreceptor reflex functions and/or study. However, the same team recently reported that
lower body venous compliance (Fortney 1991). moderate exercise performed against LBNP (52 mmHg)
HDBR experiments have been performed to assess the without post-exercise static LBNP failed to protect
effects of different protocols with LBNP sessions alone or orthostatic tolerance after 15 days of bed rest (Schneider
in combination with other countermeasures. Guell et al. et al. 2002). LBNP combined with treadmill exercise
(1991) showed that daily regular LBNP sessions at – (Fig. 4) followed by static post exercise LBNP was used
30 mmHg (three to four sessions per day, and up to six together with resistive muscle training in the exercise
sessions during the last 3 days) had beneficial effects on group of a 60-day HDBR in women (WISE-2005), which
orthostatic intolerance after a 30-day –6 HDBR, mainly by was jointly organised and funded by the European, US,
maintaining plasma and extra cellular fluid volume (Gharib French, and Canadian space agencies.
et al. 1992) with some beneficial effects on vasomotor tone
(Arbeille et al. 1992). LBNP sessions had no preventive
effects on lower limb venous distensibility and loss in
lower limb muscles (Berry et al. 1993). In another 28-day
HDBR experiment, daily LBNP sessions (15 min, –
30 mmHg) were performed during the third and fourth
week in combination with muscular exercise. The exercise
consisted of combined graded dynamic and isotonic leg
exercises, realized daily in two sessions of 15–20 min
each, 6 days per week. These countermeasures also im-
proved orthostatic tolerance (Pavy-Le Traon et al. 1995),
but the effects of LBNP and muscular exercise could not be
easily dissociated. There was probably a combined action
on plasma volume (Maillet et al. 1996).
LBNP sessions require a compromise between duration
and pressure level. A pressure of –30 mmHg is well tol-
erated, but –40 to –50 mmHg better simulate the upright
position. However, possible fainting due to reduced blood
pressure at the head level prohibits prolonged passive Fig. 4 LBNP combined with treadmill exercise in supine subjects
LBNP exposure above –50 mmHg. The bed rest experi- provides both cardiovascular and musculo-skeletal stimulation

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Aerobic exercise combination with LBNP (performed at the same time or

not) to prevent both OI and decrease in exercise capacity.
Physical exercise as a potential countermeasure against OI
is due to its positive effects on plasma volume and baro- Other physical countermeasures
reflex functions. Greenleaf et al. (1992) compared the ef-
fects of daily isotonic or isokinetic leg exercise with no Thigh cuffs are used by Russian cosmonauts to limit the
training during a 30-day HDBR and showed plasma vol- fluid shift induced by spaceflight but their effects on OI after
ume was preserved only in the isotonic exercise group. the flight are not really known. In a 7-day HDBR performed
Engelke et al. (1996) showed the benefit of a single acute in eight subjects, Pavy-Le Traon et al. (2001) showed that
maximal supine cycle ergometry exercise on OI when thigh cuffs (worn daily from 9 A.M. to 7 P.M.) limit headache
subjects were tested 24 h later after a 16-day –6 HDBR. due to fluid shift, as well as the loss in plasma volume (–
This positive effect is related to increased or restored blood 5.85 ± 0.95% with thigh cuffs; –9.09 ± 0.82% without),
volume and baroreflex functions (Convertino 1991, 1992, they also limit the tachycardia and reduction in the spon-
1996; Crandall et al. 1994; Engelke et al. 1995, 1996). taneous baroreflex sensitivity induced by HDBR (Custaud
However Moore et al. (2001) studied the cardiovascular et al. 2000) but did not influence the mean duration of the
responses to a 10-min stand test within 1–2 h of landing orthostatic tests (10 min stand test and LBNP up to –
after Shuttle flight in four crewmembers who performed 45 mmHg). Eight hours with thigh cuffs increased the
maximal exercise 24 h before landing and in four ‘‘con- cardiac and carotid sizes which is in agreement with the
trol’’ crewmembers. The investigators concluded that plasma volume increase and reduced the jugular section and
maximal exercise may have helped maintain stroke volume front head edema which may explain the sensation of
but did not influence heart rate and blood pressure re- comfort reported by the subjects (Roumy et al. 2001).
sponses during standing compared to preflight. However, The effects of standing or walking on physiological
these results are difficult to interpret since all crewmembers changes induced by HDBR (Vernikos et al. 1996) are
completed the 10-min stand tests before and after flight. discussed in Paragraph on Artificial gravity.
Obviously, physical training has been used to prevent
the decrease in exercise capacity. Thirty-day 6 HDBR was Pharmacological approaches
conducted to evaluate variable high-intensity, short-dura-
tion, isotonic cycle ergometer exercise (ITE) training and Several drugs have been tested to prevent orthostatic
high-intensity intermittent resistive isokinetic exercise intolerance with some partial effects: atropine by blocking
(IKE) training regimens designed to maintain peak VO2 vagal reflexes, propanolol, clonidine (a partial alpha-2
and muscle mass, strength, and endurance (Greenleaf 1989, agonist generally used as an anti-hypertensive agent),
1997). The ITE training regimen maintained work capacity ephedrine, indomethacin, flludrocortisone, midodrine (re-
(peak VO2), plasma and red cell volumes, induced positive view, Lathers and Charles 1994). Propanolol (a beta
body water balance and had no effect on the decrease in blocker) has been shown to have some beneficial effects
orthostatic tolerance; the IKE training regimen attenuated (Sandler et al. 1985). More recently, Takenaka et al. (1997)
the decrease in peak VO2 by 50%, the loss of red cell reported no improvement in tolerance to LBNP after a 20-
volume by 40% but had no effect on loss of plasma vol- day HDBR after intravenous propanolol administration
ume, induced positive body water balance, and had no (0.04 mg/kg). Besides the efficiency, side effects and dif-
effect on the decrease in orthostatic tolerance. ficulty of use have to be considered for drugs acting on the
No effect of a combined eccentric-concentric calf and cardiovascular system. Fludrocortisone was one of the
thigh resistance exercise (Fly wheel) performed three times most effective drugs against OI after HDBR (Vernikos and
a week (20-min every day) was observed on OI after a 90- Convertino 1994; Vernikos et al. 1991); it increases the
day HDBR (Belin de Chantemerle 2004a). plasma volume and also the responsiveness of vascular
Some studies have also shown the benefit of exercise on smooth muscle to epinephrine. Vernikos et al. (1991) also
thermoregulatory responses. Dynamic exercise (90 min/ showed beneficial effects of the combination of fludro-
day on supine cycle ergometry (75% of pre-HDBR maxi- cortisone, dextroamphetamine, and atropine. In their re-
mum heart rate)) preserved thermoregulatory responses view, Lathers and Charles (1994) concluded that the ideal
during a 14-day HDBR (Crandall et al. 2003; Shibasaki agent or combination of agents to control the hypotension
et al. 2003). This aspect of exercise on thermoregulation has not yet been defined.
must be considered, in particular with respect to extra- Midodrine seems to be a promising agent; it is an alpha
vehicular activity (Cowell et al. 2002). 1 adrenergic agonist which stimulates both arterial and
As previously discussed in ‘‘Lower body negative venous vasoconstriction (Platts et al. 2004). The positive
pressure’’ section, muscular exercise has been also used in effects of midodrine, to prevent orthostatic intolerance

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have been shown after a 16-day (–6) HDBR (Ramsdell and/or the decrease in exercise capacity. The artificial
et al. 2001). This drug acts rapidly (in 1 h) with a short gravity which acts on all physiological systems represents a
duration of action (about 4 h) and is probably easier to use promising alternative approach. However the requirements
than fludrocortisone. for use of artificial gravity (short arm centrifuge) have yet
Some possible changes in pharmacokinetics and/or to be defined.
pharmacodynamics of drugs have to be considered in space
flights and in HDBR. Some studies have already shown
changes in pharmacokinetics in HDBR. Saivin et al. (1995) Metabolism, endocrine mechanisms and nutrition
reported a decrease in maximal concentration and an in-
crease in clearance of lidocaine used as a probe to study Immobilization, as in bed rest, causes changes in energy
hepatic elimination. Gandia et al. (2003) reported more requirements, protein metabolism, insulin resistance,
rapid absorption of acetaminophen used as a probe to as- changes in the humoral regulating mechanisms and others.
sess gastric emptying During bed rest, energy requirements are reduced to the
basal metabolic rate plus a small percentage of calories
Combined countermeasures because of the energy expenditure generated by the resid-
ual small amount of movements. These activities include
The use of combined countermeasures is designed to pre- those of turning around in bed and being awake. Addi-
vent or limit adverse effects induced by real or simulated tionally, the energy needs for thermogenesis during
microgravity on multiple physiological systems. Combined digestion have to be considered. Matching the individual
countermeasures are used in spaceflights, including physi- energy requirement in immobilization is not an easy task.
cal exercise, fluid loading, anti g suit, LBNP. Some com- Most bed rest facilities are not equipped with activity
binations of countermeasures have been tested in HDBR. meters to monitor movement continuously. Measuring
The combined effects of LBNP and muscular exercise basal metabolic rate by indirect calorimetry as well as
(separately or at the same time) on cardiovascular decon- energy expenditure during any activity in bed is therefore
ditioning have been already discussed. The assessment of mandatory to match the energy needs of each volunteer.
combined countermeasures will be probably developed but However, inadequate calculation of energy needs and
raises the issue of identification of individual effects of adjustment of the caloric intake in bed rest will lead to
each countermeasure if never tested alone before. increasing fat tissue in the case of overfeeding or loss of fat
In summary, many bed rest studies have been focused and lean body mass in the case of malnutrition. During
on cardiovascular adaptation. Some elements in the regu- chronic bed rest, however, lean body mass is lost further
lation of body fluid are well known and similar in space resulting in a slow decrease in the basal metabolic rate as
flights like the decrease in plasma volume which leads to a the duration in bed increases.
well-documented set of cardiovascular changes including The following sections review data obtained during bed
impairment in baroreflex sensitivity. Fluid and salt intake rest studies of the past 20 years since 1986 and the effects
are major factors that influence body fluid and hormone of bed rest on protein and carbohydrate metabolism
changes. Besides the hypovolemia, the inability to ade- including hormonal changes, their effects on inflammatory
quately elevate vascular peripheral resistance is the most processes and changes in mineral and vitamin metabolism
important factor of orthostatic intolerance. The role of the and requirements.
endothelium which is a key factor in the regulation of the
vasomotor tone is not well known. Animal studies and Protein metabolism
indirect assessment of vascular adaptation in humans sug-
gest that the fluid shift may induce differential adaptation It is well known that loss of muscle mass and strength is
of vessels in different anatomic regions (Zhang 2001). one of the most serious problems in bed rest and space-
Reduction of exercise capacity with bed rest is well flight. With loss of muscle tissue a negative protein balance
established, depending on bed rest duration and initial level measured as nitrogen balance as well as fluid and electro-
of aerobic fitness. Few studies have dealt with pulmonary lyte losses occur. Protein loss is always of concern because
function in HDBR, probably because of the absence of a loss of 35–40% is fatal (Stein et al. 1999). When ana-
clinical events. Many countermeasures have been tested lyzing protein synthesis and protein breakdown in HDBR-
against cardiovascular deconditioning including physical (Ferrando et al. 1996; Biolo et al. 2003, 2004) and hori-
ones (lower body negative pressure, LBNP, aerobic exer- zontal bed rest (Stuart et al. 1990) it was shown during
cise alone or combined with LBNP), fluid and salt loading short-term (7 or 14 days) bed rest studies, that the loss of
and drugs. Despite some significant beneficial effects no muscle mass was caused by decreased protein synthesis
countermeasure totally prevents the orthostatic intolerance rather than increased protein breakdown (Stuart et al. 1990;

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Ferrando et al. 1996; Biolo et al. 2003, 2004). Stuart et al. (1997) analyzed glucose tolerance and insulin resistance in
(1990) increased dietary protein intake from 0.6 g/kg body a 20-day horizontal bed rest study with ten male and seven
weight/day—the adequate intake recommended by WHO female test subjects. They found that in response to the oral
at the time when the study was carried out (Garza et al. glucose tolerance test during bed rest and confirming pre-
1977; today the recommended intake level is 0.8 g/kg body vious studies in males, there was a significantly greater
weight/day to 1.0 g/kg body weight/day). They found that increase as early as day 3 of bed rest in area under the
increasing protein intake prevented the decrease in protein response curves of glucose and insulin. In male volunteers,
synthesis. Further studies by Stein et al. (1999) found that bed rest induced also a delay in the peak glucose concen-
the positive effect of increasing protein intake is most tration both during and after the end of bed rest. However,
likely due to an increased percentage of the branched-chain this was not true for the female volunteers. An increase in
essential amino acids (isoleucin, leucine and valin)—rather insulin responses in both genders has also been demon-
than to the total amount of protein. Paddon-Jones et al. strated in a 7-day bed rest study by Blanc et al. (2000).
(2004) tested a combination of 49.5 g of additional Similar results were obtained by others in trained and
essential amino acids (isoleucine, leucine, lysine, methio- untrained test subjects (Wegmann et al. 1984; Smorawinski
nine, phenylalanine, threonine, tryptophan, valin) plus 90 g et al. 1996, 2000). Following a 3-day bed rest period the
of carbohydrates as a countermeasure to the decrease in standard oral glucose tolerance test (OGTT) resulted in a
protein synthesis induced by 28 days of bed rest. With this significant increase in the blood glucose levels only in
supplement they were not only able to maintain lean leg untrained test subjects, whilst the insulin concentration as
mass; they could also show that muscle strength was less well as the insulin area under the insulin response were
decreased in the supplemented group compared to the increased in both trained and untrained test subjects. This
control group. However, the control group was no ideal was independent of the type of training regime—endurance
control since the supplement was in addition to the daily or strength training (Smorawinski et al. 2000). In addition,
meals in the bed rest group, whereas the control group did bed rest resulted in increased C-peptide levels (Mikines
not receive the equivalent isocaloric meals. et al. 1989, 1991). These effects have been interpreted as
Based on these study results increasing the intake of reduced sensitivity of inactive muscles to insulin (Mikines
branched-chain amino acids seems to have a high potential et al. 1991; Stuart et al. 1988; Blanc et al. 2000). Further
to keep up muscle protein synthesis in bed rest. However, studies carried out by Vukovich et al. (1996) demonstrated
further HDBR bed rest studies—including adequate control that reduced insulin action caused by 6-day inactivity in
measurements—have to prove whether these supplements endurance runners was associated with diminished content
would also maintain muscle strength. Additionally, a of glucose transporter protein levels (GLUT-4) in the
combination of amino acid supplementation with a con- gastrocnemius muscle. Tabata et al. (1999) investigated the
current training regime—which first needs to be individu- effects of isometric, resistance exercise training on the
ally defined and proven successful by itself—might concentration of GLUT-4 in the vastus lateralis of nine
amplify the effects of the other countermeasure. At least healthy, young male subjects during a 20-day HDT bed rest
protein synthesis rates should be further stimulated as study. (Five trained with leg presses and four served as
shown by Biolo et al. (1995b) in untrained test subjects in controls.) However, in this study the subjects were allowed
daily life. In the process of maintaining muscle strength, to get up every other day to shower. The exercising group
this countermeasure might also be useful to counteract were transported and trained in the horizontal position
bone loss in bed rest. every day and their training session lasted 3 min plus the
transport time to the lab. As expected, by the end of the bed
Insulin, insulin resistance and energy metabolism rest phase, GLUT-4 content decreased significantly (–16%;
P < 0.05) in the control group but increased in the training
Insulin is the major hormonal regulator of energy storage group (+30%; P < 0.01). The data show that, first, with
and release. It stimulates glycogen synthesis, aerobic and respect to insulin sensitivity during bed rest, athletes appear
anaerobic glycolysis, and protein and fatty acid synthesis in to benefit from their regular physical activity preceding bed
the liver. Furthermore, insulin inhibits glycogenolytic, rest deconditioning. Secondly, isometric, resistance exer-
gluconeogenic, proteolytic and lipolytic processes as well, cise training during bed rest could overcome the effect of
resulting in a net increase in energy metabolism. inactivity on GLUT-4 content during bed rest.
In numerous bed rest studies it has been shown that the However, Alonso et al (2005) showed in animal
sensitivity to insulin is decreased (Mikines et al. 1989, experiments (rats) that restriction of food intake by 50%
1991; Shangraw et al. 1988; Smorawinski et al. 1996, (not single nutrient restriction) also had an effect on
2000; Stuart et al. 1988, 1990; Yanagibori et al. 1994, GLUT-4 receptors which was different in skeletal muscle
1997; Blanc et al. 2000). As one example, Yanagibori et al. compared to adipose tissue. While in skeletal muscle such

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food restriction led to an increase in GLUT-4 receptors, in ological concentrations of IL-6 induce an anti-inflamma-
adipose tissue a decrease in these receptors was observed. tory rather than an inflammatory response in humans
These findings underline yet again the importance of ade- possibly mediated by stimulation of IL-10 secretion and
quate and proper nutrient supply—avoiding overfeeding or subsequent down-regulation of other pro-inflammatory
undernutrition—to accurately derive the true effects of bed cytokines. This mechanism could explain therefore the
rest alone. decrease in muscle TNF-alpha gene expression following
Apart from the effects of insulin on glucose metabolism, resistance exercise training in frail elderly individuals
insulin is also a regulator of protein metabolism. The (Greiwe et al. 2001).
synthesis of myofibrillar protein requires physiological It seems that bed rest leads to an increase in pro-
levels of insulin. Hyperinsulinemia caused by insulin inflammatory cytokine secretion as shown during a 113-
infusion—while holding blood amino acid concentrations day HDT bed rest study (Schmitt et al. 1996). Time-course
normal—leads to increased rates of muscle protein syn- measurements, however, are not available in this experi-
thesis without changing protein breakdown in muscle in ment.
ambulatory healthy volunteers (Biolo et al. 1995a, 1999). Secretion of IL-6 as well as the anti-inflammatory
However, in the case of decreased insulin sensitivity this cytokine IL-10 were increased when in vitro secretion of
increased protein synthesis may not take place. As in pa- these were examined in a 42-day HDT bed rest study in
tients with Type II-Diabetes (Tessari et al. 1986), bed rest healthy male volunteers (Schmitt et al. 2000). Circulating
induced insulin resistance might therefore be an added IL-10 levels were decreased on day 41. A time-course was
cause for the decreased muscle protein synthesis during also not done in this study. However, the investigators
immobilization. concluded that the increase in IL-10 was not related to the
Although the results of the mentioned bed rest studies duration of HDT. But that these effects were probably more
show indications of insulin resistance, the different study stress related (Schmitt et al. 2000).
conditions do not really allow drawing conclusions. Inflammatory processes due to other causes than bed
Training status of different test subjects lead to different rest, like hypercaloric nutrition, stress, may very well
results, gender aspects are relevant. Further very well- interact with changes induced by HDBR. Up to now, no
controlled HDBR studies are mandatory, including strict clear cut picture is available showing the interactions of
dietary conditions and gender aspects to conclude on the bed rest, other causes and cytokines. Further very well-
risk of developing insulin resistance during bed rest as well controlled studies need to be conducted to examine if
as the interaction between insulin resistance and protein HDBR per se activates pro-inflammatory processes or re-
synthesis. duces anti-inflammatory effects. All other known influ-
ences during these experiments have to be very well
Inflammatory processes controlled to reach a conclusion.

Cytokines are small biological active molecules that reg- Minerals and vitamins
ulate inflammation and have a direct effect on muscle
wasting. It is well known that some cytokines function Besides the vitamins and minerals directly involved in
primarily to induce inflammation while others suppress calcium metabolism or body fluid regulation like vitamin
inflammation. Proinflammatory cytokines like interleukin- D, calcium, phosphate (see section on ‘‘calcium and bone
1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor-a metabolism’’), sodium or potassium (see section on ‘‘car-
(TNF-a) initiate a cascade of inflammatory mediators by diovascular and pulmonary adaptation’’) etc. changes in the
targeting the endothelium. Anti-inflammatory cytokines metabolism of other vitamins or minerals are rarely
(IL-4, IL-10, IL-13) block this process or at least suppress examined in bed rest studies in humans. In recent bed rest
the intensity of the cascade. As an example, a prolonged studies in Europe as well as in the US dietary control was
exposure to IL-1 has been reported to cause anorexia, introduced. This means that the diet provided to the test
weight loss and negative nitrogen balance, suggesting that subjects should contain all the nutrients in an amount ref-
IL-1 could play a role in the metabolic alterations associ- erenced by respective national or international nutritional
ated with cachexia (Biolo and De Cicco 2004). societies and called ‘Daily Recommended Intake (DRI)’
Cytokines could also be involved in muscle protein for ambulatory, non-bedrested persons.
anabolism following resistance exercise training. Physical In order to understand the effects of bed rest on trace
exercise induces the release of a cascade of cytokines. elements only one bed rest study has been published in
Nonetheless, in response to exercise, the plasma concen- which—in a well-controlled study design—metabolic bal-
tration of IL-6 increases more than that of any other ances of copper and zinc were examined (Krebs et al. 1988,
cytokine examined. Recent evidence indicates that physi- 1993). A zinc loss occurred up to bed rest week 10 due to

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increased fecal zinc excretion while copper balance was loss of muscle mass, force and power, increased fatiga-
unaffected by bed rest. Since zinc is an essential element bility, and abnormal reflex patterns (Desplanches 1997; di
for the immune system, total body zinc loss might have an Prampero and Narici 2003). Back and leg muscles show
effect on immune function via changes in natural killer cell significant atrophy in the early weeks of bed rest (LeBlanc
activity or their functional loss (Rink and Gabriel 2000). et al. 1992). Changes in muscle size and strength, in par-
Further studies are needed to explore the interaction of ticular in leg muscles, have been studied after bed rest of
potential zinc deficiency and bed rest on immune function. various durations or after periods of unilateral lower limb
In summary, the publications on HDBR show that only a unloading (Berg et al. 1991). The results show progressive
very limited number of published HDBR studies have in- and consistent changes in both mass and function.
cluded a control group or observed standardized condi-
tions. This requires that future studies in which the Muscle mass and function
physiological changes in bed rest or countermeasures are
examined follow standardized procedures. Adequate Muscle cross-sectional area (CSA) is generally studied
nutrient intake matching closely the recommended dietary using magnetic resonance imaging (MRI) (Fig. 5). A small
intakes should be used to avoid any impact of under- or but significant decrease in thigh muscle (–3%) was re-
over-nutrition. ported even after only 7 days of bed rest (Ferrando et al.
However, nutrient supplementation might also function 1995).
as pharmacological countermeasure dependent on the The assessment of maximal contractions of the ankle
amount provided. Although vitamin D supplementation and steady submaximal isometric contractions of the ankle
might not work as a countermeasure for bone loss during and knee extensor muscles before and after a 20-day bed
bed rest (see chapter on bone), in the recent literature ef- rest study showed a considerable decrease in maximal
fects on muscle function, diabetes (Zittermann 2003; Grant torque for both the ankle extensors (9%) and knee exten-
and Holick 2005), the immunological and the cardiovas- sors (16%). The physiological CSA (PCSA) of knee ex-
cular system are discussed (Zittermann et al. 2004, 2005). tensors, knee flexors and plantar flexors decreased by 7.8,
Since bed rest as well as spaceflight are accompanied by 11.5 and 12.8%, respectively (Akima et al. 1997, 2000,
decreased 25-OH D- and 1,25-OH D levels, a first priority 2003). In a 20-day HDBR, Kawakami et al. (2000) reported
should be to examine different levels of vitamin D3 sup- a decrease in quadriceps CSA of 10% and among its
plementation as a nutraceutical to counteract several constituent muscles, the vastus intermedius was predomi-
physiological changes in bed rest. nantly atrophied. Funato et al. (1997) investigated the
force, velocity and power output of upper and lower limb
movements using a dynamometer applicable to single joint
Skeletal muscle movements. After a 20-day BR, a decrease in power as
well as a decrease in both force and velocity were observed
Gravitational load is necessary to maintain postural muscle in lower limb (by 19.8–43.6%), but not in upper limb
size and force. In humans, anti-gravity muscles of the movements. The decrease in maximal static force for knee
lower limbs and to a lesser degree of the back are the most flexors and extensors (–18.9 to –26.8%) was more pro-
affected by exposure to real and simulated microgravity. nounced than the decrease in CSA (about –7%). Abe et al.
The changes induced by microgravity consist mainly of (1997) used ultrasound as a simple non-invasive means of

Fig. 5 MRI axial images of the

human calf muscles before (b)
and after (a) 90 days of bed rest
(ESA/CNES/NASDA 90 day
HDBR, Toulouse 2001–2002)

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Fig. 6 Sagittal ultrasound

images of the human
gastrocnemius muscle before
(b) and after (a) 35 days of bed
rest (2006 Valdoltra bed rest
study, Slovenia)

measuring muscle thickness and found a high statistically ume was unchanged in the psoas, but showed losses of 9%
significant correlation between muscle thickness and CSA in the intrinsic lower back muscle group, 16–18% in the
for quadriceps assessment; they reported a decrease in quadriceps group, 21% in the ankle flexors and 30% in the
lower limb muscle thickness by 2.1–4.4% after a 20-day ankle extensors (Le Blanc et al. 1992).
BR. Ultrasound muscle measurements are illustrated in These studies collectively showed that the anti-gravity
Fig. 6. extensors of the knee and the ankle are the most affected.
After 29 days of HDBR (–6), Alkner and Tesch (2004a, Some studies showed more pronounced atrophy in plantar
b) reported a decrease in quadriceps and triceps surae flexors compared to knee extensors, but others did not.
volume of 10 and 16%, respectively. Berry et al. (1993) However, in longer duration bed rest studies, the plan-
reported a uniform loss in quadriceps CSA (11%) and tri- tar-flexors seem to be the most affected (Alkner and Tesch
ceps CSA (10.5%, deeper soleus more affected than gas- 2004a, b; Le Blanc et al. 1992). This is probably due to
trocnemius) after a 30-day HDBR. In the same bed rest their greater mechanical loading under normal gravity
subjects, Portero et al. (1996) showed a more pronounced (Reeves et al. 2002).
decrease in maximal torque for plantar flexor (20.5%) Changes in muscle function also depend on the duration
compared with dorsiflexor (15.1%) muscles. Knee extensor of bed rest and the exercise training. This was brought out
CSA decreased by 14% (vastus lateralis, 18%) and maxi- clearly by Trappe et al. (2001) when they compared the
mum voluntary isometric and concentric knee extensor effects of a 17-day spaceflight and 17 days of HDBR on
torque decreased uniformly across angular velocities by muscle fibre size, composition and contractile properties of
25–30% after 6 weeks of HDBR (Berg et al. 1997). the calf muscle using muscle biopsies and strength
In a 90-day HDBR study, Alkner and Tesch (2004a, b) assessment. Even though Ferrando had documented a small
measured knee extensor and plantar flexor muscle size and but significant reduction in thigh CSA after 7 days of strict
function. Knee extensor and plantar flexor muscle volume HDBR (Ferrando et al. 1995). Trappe et al. (2001) could
decreased by 18 and 29%, respectively. Torque or force find no changes in calf muscle strength and morphology in
and power decreased by 31–60% (knee extension) and 37– either spaceflight or HDBR. The authors concluded that the
56% (plantar flexion); EMG activity decreased 31–38% sequence of tests used during the spaceflight and the
and 28–35%, respectively. In the same study, Rittweger HDBR (three times) may have served as an effective
et al. (2005) reported a significant decrease in calf muscle resistance training countermeasure to attenuate muscle
CSA (–25.6%) (illustrated in Fig. 5) but not in forearm strength loss. It is intriguing to believe that three tests over
CSA (–6.4%). In a 120-day HDBR, Koryak (1998a, b) 17 days would have completely prevented the effects on
found a decrease in maximal voluntary contraction of the muscle of microgravity and bed rest. This point dealing
triceps surae of 36%. The effects of 2 and 4 months of bed with the way and rate of testing must be carefully con-
rest, with or without exercise countermeasures, on the sidered in the design of BR studies.
contractile properties of slow fibres in the human soleus Only one group of investigators looked at the adductor
muscle were also examined by Yamashita-Goto et al. muscle group and showed that the amount and the pattern
(2001). These results indicate that long-term bed rest re- of the relative change in the PCSA induced by a 20-day BR
sults in reduced fibre size, force-generation capacity, and were similar to those of the knee extensor and knee flexor
Ca2+ sensitivity, and enhanced shortening velocity in slow muscle groups (Kawashima et al. 2004). These authors
fibres of the soleus. recommend that more attention should be paid to the
Few studies looked at the changes of the muscles of the adductor muscle group when considering countermeasures
back. After 17 weeks of horizontal bed rest, muscle vol- for long duration flights.

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Mechanisms of loss in muscle strength as in the muscle fibres. Yamanaka et al. (1999) found
strong inhibition of the H-reflex and no adaptation of the
The greater relative decrease in maximal strength than size motor evoked potential in the soleus muscle in response to
shown in these studies suggests that atrophy alone cannot transcranial magnetic stimulation when standing after a 20-
account for the strength loss. Altered motor control, day HDBR period.
changes in the properties of the contractile machinery and However, Ferretti et al. (2001) compared the reduction
reduced efficiency of the electromechanical coupling may in maximal instantaneous muscular power (assessed on a
contribute to the loss of strength. force platform) and the reduction, in thigh extensors CSA
Therefore several studies aimed to point out changes in after a 42-day HDBR (–23.7 and –16.7%, respectively). By
neuro-motor control. Koryak (1998a, b) showed that the normalizing the maximal instantaneous muscular power for
functional properties of the triceps surae muscle changed CSA, they concluded that the reduction in power is mainly
considerably after a 120-day –6 HDBR. The maximal explained by the reduction in CSA and than other factors
voluntary contraction (MVC) decreased by 36%, the such as a deficit in neural activation or a decrease in fibre-
electrically evoked tetanic tension at 150 Hz (Po) and specific tension may account for only 5% of the power loss.
isometric twitch contraction (Pt) decreased by 24 and 12%, The role of neural versus muscular changes was also
respectively. The force deficit (corresponding to the dif- evoked after spaceflights; the large decrease in maximal
ference between Po and MVC and expressed as a per- power (after 1 and 6 months) compared to the decrease in
centage of Po) increased by 40%. Time to peak tension, muscle mass is probably due to a deterioration of the motor
half relaxation time and total contraction time increased coordination induced but microgravity (di Prampero and
significantly. The rate of increase in voluntary contraction Narici 2003).
was significantly reduced, but no substantial change was Tendon mechanical properties have also been studied.
reported in electrically evoked contractions. Muscle fati- Kubo et al. (2004a, b) investigated the tendon properties in
gability also increased. From these observations, the au- knee extensors and plantar flexors using ultrasonography
thors suggested that the changes of contractile properties of during ramp isometric contraction, followed by ramp
the triceps surae are linked on one hand to atrophic pro- relaxation. In order to assess tendon stiffness, they studied
cesses and alterations of muscle length, and on the other the relationship between muscle force and tendon elonga-
hand to altered neural adaptation. However, no study has tion. Tendon stiffness significantly decreased after 20 days
yet demonstrated a change in muscle length with actual or of bed rest in knee extensors but not in plantar flexors. In
simulated microgravity in humans. contrast after 90 days of HDBR, Reeves et al. (2005) found
Increased fatigability was also reported by Portero et al. tendon stiffness of the gastrocnemius had decreased by
(1996) after a 4-week HDBR; this was more pronounced 57% as estimated by ultrasound imaging from the gradient
for plantar-flexor compared to dorsi-flexor muscles. of the tendon force-deformation during isometric plantar
Alterations in motor control were indicated by decreased flexion (Fig. 7). This seems to be consistent with the
EMG amplitude during maximal and increased amplitude finding of decreased tendon stiffness in chronic disuse due
during sub-maximal contractions. An increase of muscle to paralysis (Maganaris et al. 2006) and suggest that
use for a given task has been also reported after real or changes in tendon stiffness occur beyond 3 weeks of dis-
simulated weightlessness reflected by increased EMG use. In contrast, Lambertz et al. (2001) showed an increase
surface amplitude or contrast shift of MRI (Ploutz-Snyder in musculotendineous stiffness after prolonged spaceflight.
et al. 1995; Berg and Tesch 1996). Kawakami et al. (2001) As suggested by di Prampero and Narici (2003) such dis-
studied neural activation using a supramaximal twitch crepancy may be due both to the different methods of
interpolated over voluntary contraction during knee evaluation of stiffness and to the different conditions of bed
extension. Smaller activation was observed after a 20-day rest (no exercise) compared to space flight (daily counter-
HDBR. The investigators also measured changes in force measures).
and in PCSA, and concluded that changes in force were
more related to changes in neural activation levels than Muscle biopsy data
those in PCSA. Ruegg et al. (2002, 2003) recorded the
surface electromyogram (EMG) of the soleus muscle at Histological, biochemical and molecular changes have
different torque levels and the direct muscle responses (M been studied on muscle biopsy tissue. Many have been
responses) to supramaximal stimulation of the posterior performed on animals. A transition from slower to faster
tibial nerve after a bed rest of several months and a pro- muscle fibre types following hind-limb suspension as well
longed stay in space (surface EMG only). They concluded as spaceflight has been documented in lower mammals
that spaceflight and bed rest resulted in a reduction of the (Ohira et al. 1992; Fitts et al. 2000). Studies in both rats
conduction velocity in the branching axon terminals as well and humans demonstrate a rapid loss of cell mass in

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myofibrillar protein content per muscle cell volume in re-

sponse to HDBR (Larsson et al. 1996). V0 did not change
when all muscle cells were pooled. Neither type I, IIA, and
IIB fibre percentages nor their relative proportions of MHC
isoforms were altered by bed rest (Berg et al. 1997).
However, in two subjects V0 decreased in muscle cells
expressing the beta/slow (type I) MHC isoform showing
different susceptibility to HDBR. By using combined
in situ hybridization, immunochemistry and ATPase his-
tochemistry, Andersen et al. (1999) showed alterations in
MHC gene expression, resulting in combinations of mRNA
and MHC isoforms normally not—or very rar-
ely—observed in muscles subjected to load-bearing activ-
ity. However, 37 days of HDBR were not sufficient to
induce similar changes at protein level. In the same study, a
deltoı̈deus muscle biopsy was also performed showing no
major morphological and biochemical changes (Desp-
Fig. 7 Gastrocnemius tendon’s Young’s modulus (stiffness norma- lanches et al. 1998).
lised to tendon dimensions) before (Pre) and after (Post) 90 days of After 2 or 4 months of HDBR, the mean size of type I
strict bed rest (ESA 2001–2002 Toulouse bed rest study) with (BREx) fibres in soleus fibres decreased by 12 and 39%, respec-
and without (BR) resistive exercises (eccentric/concentric contrac-
tions with flywheel ergometer)
tively, and a tendency towards a higher percentage of fibres
expressing fast MHC isoforms and a de novo appearance of
fibres coexpressing type I + IIa + IIx and IIa + IIx MHC
microgravity. For both species, the antigravity soleus was observed (Ohira et al. 1999, 2000; Yamshita-Goto
muscle showed greater atrophy than the fast-twitch gas- et al. 2001).
trocnemius. However, in the rat, the slow type I fibres Muscle biopsies were also obtained from the vastus
atrophied more than the fast type II fibres, while in humans, lateralis (n = 9) and the soleus (n = 3) before and after
the fast type II fibres were at least as susceptible to space- 84 days of HDBR (ESA/CNES/NASDA 90-day HDBR).
induced atrophy as the slow fibre type (Fitts et al. 2001). Atrophy was detected in mixed, fast and slow vastus lat-
Soleus biopsies performed on four male astronauts after a eralis (VL) and slow-type soleus (SOL) myofibre types I
17-day spaceflight (Trappe et al. 2001; Widrick et al. 1999, and II (minus 35–40% of myofibre cross-sectional area)
2001) demonstrated that (1) slow and fast gastrocnemius (Rudnick et al. 2005). MHC shifts were observed. In VL,
fibres show little atrophy and loss of peak Ca2+ activated MHC I (16%) and MHC II a (14%) decreased by 16 and
force (P0) but increased mean velocity of shortening (V0), 14%, respectively. There were 10% increases in MHC I/
(2) there is considerable intersubject variation in these re- IIa, IIa/IIx, I/IIa/IIx and total hydrid fibres increased by
sponses, possibly due to intersubject differences in in-flight about 30%. In SOL, MHC I decreased by 19% and total
physical activity, and (3) fibre atrophy and reductions in hydrid fibres increased by about 30% (Gallagher et al.
P(o) were less for slow and fast fibres obtained from the 2005). MHC I and IIa fibres were, respectively, 15 and 8%
phasic fast-twitch gastrocnemius muscle compared with smaller, 46 and 25% weaker (Po), 21 and 6% slower (VO),
slow and fast fibres obtained from the slow anti-gravity and 54 and 24% less powerful after bed rest. MHC I and IIa
soleus. The authors concluded that 17 days of spaceflight Po and power normalized to cell size were lower (Trappe
decreased force and increased shortening velocity of single et al. 2004).
Ca2+-activated muscle cells expressing type I MHC As nitric oxide (NO) signalling is linked to muscle
(myosin heavy chain) and that the increase in shortening activity, Rudnick et al. (2005) investigated altered
velocity greatly reduced the impact that impaired force expression of the three major isoforms of nitric oxide
production had on absolute peak power. synthase (NOS 1–3) in cellular compartments Concomitant
Muscle biopsies from the vastus lateralis were per- to muscle atrophy, reduced NOS 1 protein and immuno-
formed before and after 37 days of HDBR in seven male staining was found in VL but not in SOL biopsies. Twelve
volunteers. Maximum force normalised to cross-sectional proteins (dystrophin and its associated proteins (DGC),
area (specific tension), maximum velocity of unloaded dysferlin, talin, vinculin and meta-vinculin, alpha-actinin,
shortening (VO) and myosin heavy chain (MHC) and light desmin, actin, and myosin), which play an important role in
chain (MLC) were studied. In response to HDBR specific muscle structure, fibre cohesion, cell integrity maintenance,
tension was reduced by 40% with a parallel decline in and force transmission, were also quantitatively analyzed

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in these VL and SOL muscle biopsies (Chopard et al. resistance exercise could prevent muscle atrophy and
2005). After HDBR, proteins belonging to the DGC, dys- strength of knee extensors. Ellis et al. (1993) during a 30-
ferlin, and proteins of the costamere exhibited large in- day HDBR showed that intensive, alternating, isotonic
creases, higher in SOL (from 67 to 216%) than in VL (from cycle ergometer exercise training (ITE) in seven subjects
32 to 142%). The authors suggest that these changes are was as effective as intensive, intermittent, isokinetic
probably related to plasma membrane remodelling during exercise training (torque ergometer) (IKE) in another seven
muscle atrophy; other mechanisms as membrane repair subjects as compared to five non-exercising controls, in
may be implicated. maintaining thicknesses as measured by ultrasonography of
rectus femoris and vastus intermedius anterior thigh mus-
Susceptibility to injury cles but not of posterior leg muscles. However, in this
study, the same team showed that while ITE training can
Studies in animals showed that anti-gravity muscles that maintain some isokinetic functions during BR, maximal
are reloaded subsequent to hindlimb unloading (HU) are intermittent IKE training could increase other functions
prone to injury (Vijayan et al. 2001; Prisby et al. 2004). above pre-BR control levels (Greenleaf et al. 1994). Ger-
Muscle weakness may also arise from possible muscle main et al. (1995) investigated in a 28-day HDBR the ef-
damage due to reloading in one g. Narici et al. (2003) fects of intense daily isometric and isokinetic leg exercise
found significant changes in muscle function (human tri- (30–45 min each day, isometric actions performed for 5–
ceps surae) during the recovery phase, but not in micro- 30 s at 90, 120 and 150 knee angles and isokinetic
gravity after a 17-day spaceflight. They concluded that the training at speeds of 30 and 180 s–1) on quadriceps muscle
disproportionate loss of torque compared with that of strength. The study included a control group of six men and
muscle in size suggests the presence of muscle damage due another six who exercised during HDBR. Physical training
to reloading in 1 g. was combined with lower body negative pressure (LBNP)
An increased susceptibility to exercise-induced damage performed at different times. The results showed a signif-
during bed rest and unloading must also to be considered icant reduction in the muscle force (–10.3%) in the control
(Prou and Marini 1997). This is particularly evident during group and no significant change in the trained group
the recovery period when subjects become once more (+3.9%).
ambulatory as well as a result of muscle testing at the end Resistance training has also been tested for its ability to
of the BR period. Inflammation appears to play an prevent atrophy and the decrease in strength of plantar
important role in the repair and regeneration of skeletal flexors. Akima et al. (2001, 2003) showed that dynamic
muscle after damage. Dennis et al. (2004) showed that IL-1 leg press and plantar flexion resistance training during bed
genotype is associated with the inflammation of skeletal rest maintains muscle size and function (torque and T2)
muscle following acute resistance exercise which may during a 20-day HDBR. Shinohara et al. (2003) looked at
potentially affect the adaptation to chronic resistance the effects of these dynamic calf-raise and leg-press
exercise. exercises on maximal contractions and steady submaximal
isometric contractions of the ankle extensor muscles and
Countermeasures of the knee extensor muscles. The results indicate that
fluctuations in torque during submaximal contractions of
Physical training the extensor muscles in the leg increase after bed rest and
that strength training counteracted the decline in perfor-
Physical training is obvious and the first countermeasure mance. However, the response varied across muscle
proposed to prevent muscle atrophy and loss of strength groups with a greater reduction in coefficient of variation
induced by inactivity in flight or bed. However, very soon in knee extensors compared to ankle extensors. Bamman
the considerable contribution of unloading to these muscle et al. (1997, 1998) also reported that a constant resistance
changes became apparent. Different types of muscular concentric/eccentric exercise training (5 sets · 6–10 rep-
exercise have been tested in HDBR (review, di Prampero etitions to failure of constant resistance concentric/
et al. 2001). In this review, the authors concluded that eccentric plantar flexion every other day) completely
whereas medium-intensity cycling exercise may be effec- prevented the decrease in plantar flexor performance in-
tive in counteracting cardiovascular deconditioning, high duced by 14 days of HDBR (n = 8 in each group).
intensity muscle loading by resistive and/or explosive Shackelford et al. (2004) showed that intensive resistance
exercise seems particularly promising for the prevention of exercise partially prevented the decrease in volume of
muscle atrophy and weakness. soleus and gastrocnemius during a 17-week horizontal bed
Resistance exercise is known to increase maximal rest study (n = 9 in the countermeasure group, n = 18 in
muscle strength. Several BR studies have shown that the control group).

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More recently, in the ESA/CNES/NASDA 90-day training and even earlier changes (within 10 days of
HDBR study, the effects of both plantar flexor and knee training) in muscle architecture.
extensor resistance exercise on muscle size and function The response to strength training varies between
were compared in 17 healthy men with (n = 8) or without individuals and has been found to be influenced by ge-
(n = 9) resistance training (Alkner and Tesch 2004a, b). netic variables. For instance, Folland et al. (2000) re-
The resistance exercise program consisted of coupled ported that angiotensin-converting enzyme (ACE)
maximal concentric and eccentric actions in the supine genotype affects the response of human skeletal muscle
squat (four sets of seven repetitions) and calf press (4 · 14) to functional overload. These authors found that the gain
every third day employing a gravity-independent flywheel in muscle strength was dependent on the presence rather
ergometer (FW) (Fig. 8). Muscle atrophy was prevented in than the absence of the D allele of the ACE genotype. It
knee extensors or attenuated in plantar flexors (–15%) in has been postulated that the ACE gene directly modu-
the countermeasure group. Resistance exercise maintained lates the response to functional overload through the
task-specific force, power and EMG activity. The decrease systemic or local muscular renin-angiotensin system by
in non-task-specific torque was less than in controls (Alk- generation of angiotensin II or breakdown of kinins.
ner and Tesch 2004a, b). At the cell level, the data showed These mechanisms are known to operate in the hyper-
that the contractile function of the MHC I fibres was more trophic response to functional overload of cardiac muscle
affected by bed rest and less influenced by the resistance and it is suspected that they may also apply to skeletal
exercise protocol than the MHC IIa fibres (Trappe et al. muscle. For instance, skeletal muscle fibre cross-sectional
2004). These authors suggested that considering the large area has been found to be correlated to the quantity of
differences in power of human MHC I and IIa muscle fi- mRNA ACE transcripts. Also, angiotensin II has been
bres (five- to sixfold), the maintenance of whole muscle shown to affect both sympathetic and neuromuscular
function with the resistance exercise programme is proba- transmission, and may thus be involved in the well
bly explained by (1) the maintenance of MHC IIa power known influence of neural adaptations to strength training
and (2) the shift from slow to fast (MHC I –> MHC I/IIa) in (Narici et al. 1989) or disuse.
single fibre MHC isoform composition. Concerning the effects of resistance training on tendon
In the same countermeasure group, there was an in- properties, although the exercise countermeasures did
creased capillary-to-fibre (C/F) ratio and NOS 3 protein attenuate the decrease in gastrocnemius tendon stiffness,
content in vastus lateralis (Rudnick et al. 2004). they did not completely prevent it (Reeves et al. 2005).
The effectiveness of flywheel training in promoting These investigators suggested that the total loading volume
muscle hypertrophy (potentially representing an effective was not sufficient to completely prevent alterations in
means for combating atrophy), is also confirmed by a re- tendon mechanical properties. In contrast, Kubo et al.
cent study of Seynnes et al. (2007) which showed signifi- (2004a, b) found that leg-press training prevented the de-
cant quadriceps hypertrophy after only 3 weeks of resistive conditioning of the tendon structures in knee extensors.
These results suggest that, similar to the lower respon-
siveness of the plantarflexor compared to the knee extensor
muscles to resistance exercise in ambulatory and bed rest
subjects, the adaptability of the Achilles and patellar ten-
dons to chronic loading may also differ.
Back pain is frequently reported in both spaceflight and
bed rest. The results of the studies performed by Baum and
Essfeld (1999) must be mentioned. These have focused on
mechanisms and prevention of the back pain. Until re-
cently, studies concentrated mainly on changes in the
length of the spine. These investigators concluded that back
pain during bed rest is induced by reduced amplitudes of
spine movements rather than by increases in the spine
length. They suggested that isometric muscle contractions
of low intensity are a primary cause of back pain and that
regular, slow, large-amplitude movements of the spine are
recommended as a countermeasure.
Besides effectiveness, tolerance, acceptance and psy-
Fig. 8 Flywheel resistance training as performed during the ESA/ chological aspects of the physical training must be con-
CNES/NASDA 90-day HDBR study sidered.

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Eur J Appl Physiol (2007) 101:143–194 171

Electrical stimulation The Mechanostat

Mechanical
Few studies dealt with electrical stimulation. In a review, di Usage Mechanostat
Prampero et al. (2001) reported the use of transcutaneous
electromyostimulation given twice daily, using a 3-day on
and 1-day off regimen in a 30-day bed rest. The results Modeling/
Bone Minimum Effective
showed smaller decreases in strength and muscle mass. Strain Mechanisms Remodeling
However, they concluded that the discomfort and the fact that
normal recruitment order of the motor units is not respected - hormones Bone mass
make this technique too preliminary to be proposed in space. - nutrition
- biochemical messengers
- disease genetic
Penguin suit - toxic agents
The effects of wearing an anti-gravity device (Penguin suit), Fig. 9 The mechanostat (see corresponding text)
which had a modest but continuous resistance at the knee and
ankle (Penguin-1) or knee resistance without loading on the bed rest is the absence of mechanical loading of the lower
ankle (Penguin-2), for 10 consecutive h/day were determined extremities. Bed rest is therefore appropriate as a model to
during 2 months of bed rest (Ohira et al. 1999, 2000; Ya- study the changes of the musculoskeletal system in
mashita-Goto et al. 2001). Fibre size and contractile prop- microgravity. However, the magnitude of bone loss in bed
erties during bed rest were maintained in the Penguin-1 but rest seems to be less than in spaceflight (LeBlanc et al.
not prevented in the Penguin-2 group, although the degree of 1990a; LeBlanc et al. 2000; Baecker et al. 2003; Smith
the changes was less than those induced by bed rest without et al. 1998).
any countermeasure. Neither group showed phenotype
changes. The results showed that a single daily 10-h bout of Physiological adaptation
modest muscle loading can prevent bed rest-induced soleus
fibre atrophy but has minimal effect on myosin phenotype. It has been long recognized that bones are genetically
Nutritional, metabolic and hormonal aspects of coun- (Galilei 1638; D’Arcy Thompson 1917) and physiologi-
termeasures to muscle atrophy are discussed in the section cally (Wolff 1899; Goodship et al. 1979) adapted to the
dealing with Nutrition and Metabolism. loads they need to bear. The first sound theory to describe
In summary, bed rest induces loss of muscle mass, force this adaptive process was proposed by Harold Frost as the
and power, increased fatigability, and abnormal reflex mechanostat theory (Frost 1987a, b, 2003; Frost and
patterns. The back and leg muscles are the most affected. Schonau 2000; Fig. 9). This theory suggests that, in a
Besides atrophy, altered motor control, changes in the manner analogous to the thermostatic control of tempera-
properties of the contractile machinery and reduced effi- ture, the strain (i.e. deformation) in bone is kept within
ciency of the electromechanical coupling probably con- certain thresholds. If the strains exceed the upper threshold,
tribute to the loss of strength. Increased susceptibility to then modelling-driven bone formation drifts (Frost 1990a)
exercise-induced damage has to be considered particularly will increase bone mass and strength. Conversely, if the
during re-loading in the recovery period. Muscle biopsies strains permanently remain below the lower threshold, then
performed after long term bed rest showed an atrophy in remodelling (Frost 1990b) is enhanced. This implies (i) an
mixed, fast and slow vastus lateralis and slow-type soleus increased activation rate of so-called basic multicellular
myofibre types I and II and an increase in total hydrid units (BMUs), i.e. ensembles of osteoclasts and osteoblasts
fibres. Physical training is the first countermeasure pro- to carry out the remodelling process, and (ii) a negative
posed to prevent muscle atrophy and loss of strength, bone balance to the incomplete filling of the resorption
particularly high intensity muscle loading by resistive and/ cavities. Consequently, bones become stronger when the
or explosive exercise. The effects of artificial gravity, force they experience is increased, and they become
possibly combined with physical exercise, seem particu- weaker when their loading is reduced.
larly promising and warrant investigating. It is important to realize that the largest forces that bones
are subjected to do not arise from gravity per se, but from
the action of muscles, often working against gravity. This
Calcium and bone metabolism is mainly due to the short levers against which muscles
work (Özkaya and Nordin 1998).
Mechanical unloading of bones results in a pronounced loss Obviously, this mechanostat hypothesis can well explain
of bone mass. The strongest stimulus for bone loss during the bone loss that is observed after unloading bones, as

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occurs after a stroke (Jorgensen et al. 2000), after spinal 1987; Vico et al. 1993; Vico et al. 1998; Uebelhart et al.
cord injury (Griffiths et al. 1976; Biering-Sorensen et al. 2000; Zerwekh et al. 1998).
1990; Eser et al. 2004), after anterior cruciate ligament In most bed rest studies calcium excretion and bone
injury (Sievanen et al. 1994a; Leppala et al. 1999), and also resorption markers (Vernikos et al. 1996; Zerwekh et al.
during bed rest (Donaldson et al. 1970; LeBlanc et al. 1998; Baecker et al. 2003) promptly increase after the onset
1990b; Zerwekh et al. 1998) and spaceflight (Vogel and of immobilization (Baecker et al. 2003; Inoue et al. 2000;
Whittle 1976; Oganov et al. 1992; Vico et al. 2000a). As Kim et al. 2003; Lueken et al. 1993; Nishimura et al. 1994;
the bone loss observed in all of these examples is very Smith et al. 1998) while for bone formation markers the
similar, bed rest studies are a well-accepted analog to results are rather inconsistent. For monitoring the need and
spaceflight. Bones also play an important role in calcium effectiveness of treatment, results from spinal cord injury
homeostasis. Accordingly, it was initially thought that the patients and postmenopausal women support the use of bone
increased calcium excretion during spaceflight and bed rest resorption markers as first indicators for patients at a high
reflected some kind of primarily endocrine disorder (Ar- risk of developing osteoporosis, such as hemiplegic or
naud and Morey-Holton 1990). However, supplementation quadriplegic patients (Maimoun et al. 2002). Resorption
of either calcium or vitamin D, or both, during bed rest markers are also used as a predictor of the long-term re-
cannot prevent bone loss (Heer et al. 1999; Heer 2002). sponse to countermeasures such as hormone replacement
This underscores the notion that mechanical usage is cru- therapy in postmenopausal women (Bjarnason and Chris-
cial for the maintenance of bone. tiansen 2000; Maimoun et al. 2002). However, biomarkers
Patterns of bone loss depict a large inter-individual of bone turnover are often criticized for their high coefficient
variability during bed rest (Watanabe et al. 2004b; Ritt- of variation of 20–55% even in a single individual (Hannon
weger et al. 2005) as well as during spaceflight (LeBlanc and Eastell 2000). Part of this variation is due to the diurnal
et al. 2000; Vico et al. 2000b). Moreover, a huge variability rhythm (Gertz et al. 1998; Greenspan et al. 1997; Hannon
has also been shown to occur at different levels of the same and Eastell 2000) of bone turnover markers which is often
bone (tibia) within individuals (Rittweger et al. 2005). This not taken into account. This variation can be reduced in
suggests that, probably, the mechanostat is not the only research studies by choosing a standardized and well-con-
factor that influences bone loss during the acute phase of trolled crossover study design, including 24 h urine collec-
immobilisation. On the other hand, observations in patients tions and drawing blood at the same time of day under
after spinal cord injury show that, in the course of years, identical conditions. In this way, the intraindividual day-to-
bone loss is quite uniform across individuals (Eser et al. day coefficient of variation can be lowered to less than 12%
2004) (Heer M. et al., unpublished data). On the other hand, the
practice of normalizing bone resorption marker excretion
Methodological approaches relative to creatinine excretion as is routinely done in clin-
ical set-ups, may alter or obscure findings and should not be
The effects of immobilization on bone can be studied by applied in any research setting (Smith et al. 2004).
using biochemical parameters, by histomorphometry on In summary, biochemical markers constitute a valuable
bone biopsies, or by radiological techniques. Using these tool to rapidly monitor changes in bone metabolism, but
techniques bone turnover markers reflecting the changes in they do not allow for quantitative estimates of bone loss,
bone formation and bone resorption processes in immobi- nor do they permit inferences as to the location of bone
lization become obvious (Baecker et al. 2003; Inoue et al. loss. In order to achieve this, radiological methods have to
2000; Kim et al. 2003; Zerwekh et al. 1998; Vico et al. be applied.

Fig. 10 Leg p QCT

measurement. A typical distal
tibia epiphysis (at 4% of its
length) is shown on the right

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Eur J Appl Physiol (2007) 101:143–194 173

Nowadays, radiological methods include Dual-Energy- Now, genetic studies indicate that 60–70% of the vari-
X-ray-Absorptiometry (DXA), Quantitative Computer ability in BMC or aBMD can be accounted for by genetic
Tomography (QCT) or peripheral QCT (pQCT) (Fig. 10) variation (Prentice 2001). Further analysis suggests that
and quantitative ultrasound (QUS). DXA, QCT and pQCT genetic predisposition, in addition to other variables, may
can reliably and accurately measure the bone mineral lead to different levels of peak bone mass, body size and
content (BMC) (Krishnan et al. 1993; Sievanen et al. possibly influence countermeasure effectiveness on BMC
1994b; Sievanen et al. 1998). However, as to the validity of and BMD as well as bone strength. Variations in envi-
these methods, it should be pointed out that DXA yields ronmental factors (exercise, diet etc.) contribute 30–40% to
only areal BMD (aBMD) while QCT and pQCT assess total phenotypic variance in bone mineral mass or BMD
volumetric BMD (vBMD). Consequently, QCT or pQCT (Prentice 2001). In addition, the influence of diet on bone
can predict whole bone strength of long bones better than health may depend on the genotype of the individual.
DXA (Wilhelm et al. 1999; Martin et al. 2004; Lochmuller Genetic predisposition may also explain the variability in
et al. 1998; Jarvinen et al. 1998). Moreover, QCT and the response to unloading. For short-term bed rest studies it
pQCT can discern between trabecular bone and compact is therefore strongly suggested to reduce the impact of
bone, which is advantageous in the study of the effects of genetic predisposition by studying volunteers in a cross-
immobilization, where the bone loss is most pronounced in over study design and where possible obtaining genetic
trabecular bone (Eser et al. 2004; Rittweger et al. 2005). information or at the very least, family histories.
LeBlanc et al. showed in a 17-week horizontal bed rest
study in healthy volunteers -in which the test subjects were Pharmacological countermeasures
allowed to sit up for bowel movements- that aBMD mea-
sured in the whole body, lumbar spine, femoral neck, tro- Bone loss in peri- and postmenopausal women is mainly
chanter, tibia, and calcaneus decreased significantly caused by reduced estrogen secretion (Schiessl et al. 1998)
compared to the baseline (P < 0.05) by 1.4, 3.9, 3.6, 4.6, (Fig. 11a, b). However, in bed rest or other forms of
2.2%, and pas respectively (LeBlanc et al. 1990a). Similar immobilization, increased bone turnover is mainly caused
results were obtained in another 17-week horizontal bed by a reduction in mechanical loading. In recent years,
rest study (Shackelford et al. 2004). However, in shorter treatment with bisphosphonates has been shown to be po-
studies, DXA analysis did not show changes in aBMD tent in reducing bone resorption and thereby maintaining or
(Suzuki et al. 1996; Uebelhart et al. 2000; LeBlanc et al. even increasing BMD in postmenopausal women. The in-
1987). In a 90-day HDBR study Rittweger et al. used crease was up to +4% in proximal femur BMD over a
pQCT to measure BMC in a resistive exercise group and period of 2 years compared to a placebo (+0.3%) group
the corresponding control group (Rittweger et al. 2005). which received calcium only (Bone et al. 2000). Bis-
Resistive exercise was carried out using a flywheel device phosphonates were therefore tested in healthy male and
adapted to 6 HDT (Alkner and Tesch 2004a, b). The female volunteers in several bed rest studies. As in post-
exercise regime consisted of four sets of seven maximal menopausal women, bisphosphonates were reported to re-
concentric and eccentric actions every third day. In the duce bed rest-induced bone loss (Chappard et al. 1989;
control group, BMC decreased significantly by 6% in the Grigoriev et al. 1992; LeBlanc et al. 2002; Ruml et al.
distal tibia epiphysis whereas only by 2.8% in the flywheel 1995; Watanabe et al. 2004b; Rittweger et al. 2005).
group. Although flywheel exercise on average counteracted
BMC loss by about 50%, a significant difference between
the exercise and control group could not be established
(Rittweger et al. 2005). The authors concluded that this was
most likely due to large inter-subject variation (Rittweger
et al. 2005). This interpretation is supported by reports in
patients who underwent hip surgery and as a consequence
were immobilized for 2 to 4 months. Ito et al. (1999)
examined vBMD in the tibia in 11 patients undergoing hip
surgery, including 10 women (22–61 years; mean ± SD =
42.6 ± 10.3) and 1 man (61 years). Two months after
surgery the vBMD was at its minimum in trabecular and
cortical bone. It was decreased by 7% in distal trabecular Fig. 11 a 3D microarchitecture of a normal bone; b 3D microarchi-
tecture of an osteoporotic bone. The images are from human vertebrae
bone and by 6% in total (trabecular and cortical) distal autopsies, normal and osteoporotic female, age 24 years (a) and
bone area compared to their baseline values before surgery 84 years (b). Scanned on SCANCO lCT 20, at 14 (m (SCANCO
(Ito et al. 1999). Medical)

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However, although under ideal conditions these com- clined comparable to the untreated control group. This is in
pounds might even maintain BMC in bed rest (Rittweger contrast to results from animal studies, such as rats in hind-
et al. 2005), it still needs to be shown that they also limb suspension. In an animal study the effect of testos-
maintain bone strength. terone administered in a controlled study design in 20
There is anecdotal evidence that, despite the fact that b2- twelve week old Wistar rats (10 placebo controlled ani-
adrenergic transmission seems to enhance osteoclastic mals, 10 animals in the testosterone group) during 12 days
activity (Elefteriou et al. 2005), systemic administration of of hindlimb suspension (Wimalawansa et al. 1999). They
b2-agonsists has surprisingly been reported to reduce dis- found that testosterone administration during hindlimb
use-related bone losses (Bloomfield et al. 1997). Using a suspension was able to maintain muscle mass. Concur-
unilateral limb-suspension model in humans the effect of rently, BMD analysed by MRI, was increased by 85% in
resistive exercise with or without administration of the b2- the testosterone group compared to the control animals. In
agonist albuterol during a 40-day experiment was exam- hypogonadal men, testosterone treatment significantly in-
ined (Caruso et al. 2004). The outcome of the study is creased BMC/BMD (Finkelstein et al. 1989; Devogelaer
unclear, as there was no control group and the placebo et al. 1992) and maintained cancellous bone mass and
group showed no change in BMC or lean mass of the integrity (Lindberg et al. 2005). However, it remains to be
suspended limb, as assessed by DXA. In the albuterol seen whether testosterone injection may also prove useful
group, a 2–3% increase was reported both for lean mass in immobilization.
and BMC. It is therefore at present uncertain whether this Other pharmacological agents like selective estrogen
apparent benefit of albuterol is real or due to the difficulty receptor modulators (SERM), parathyroid hormone (PTH)
of discerning lean mass and BMC using DXA. and strontium ranelate have been successfully tested and
The results of several clinical studies led to the con- found to decrease the risk of vertebral and non-vertebral
clusion that high levels of nitric oxide (NO) cause bone fractures in postmenopausal women (Delmas et al. 2002;
resorption as a result of inflammatory processes. In con- Roux et al. 2006; Weinstein et al. 2003; Neer et al. 2001).
trast, lower doses of NO on one hand inhibit bone-re- During immobilization as in spaceflight or bed rest, how-
sorbing activity (van’t Hof and Ralston 2001; Damoulis ever, PTH seems to be the most promising, since PTH is
and Hauschka 1997) and on the other hand activate bone the only anabolic agent approved for the treatment of
formation (Wimalawansa 2000; Ralston 1997). The re- osteoporosis (Cosman 2005). PTH should therefore be
sponse of bone cells in culture to the shear forces of fluid tested in immobilization studies as well, because it may
flow includes rapid production of nitric oxide (NO) as a very well increase bone formation.
result of activation of endothelial nitric oxide synthase
(ecNOS) (Klein-Nulend et al. 2003). NO can be generated Exercise countermeasures
pharmacologically by NO-Donors which are clinically used
as vasodilators. A pharmacological study in 1026 oste- There is ample evidence for the crucial role that mechan-
openic perimenopausal women recently completed at the ical loading per se plays in bone health (Rubin and Lanyon
University of Turin, Italy, showed a significant decline in 1987). Since bed rest is inevitably coupled with reduced
bone resorption markers (Press release by NICOX, July 11, mechanical loading, using various exercise regimes to
2005; http://www.nicox.com) by more than 40% in 24% of overcome the effects of unloading and maintain bone mass
the evaluated volunteers receiving the specific NO-donor seems a reasonable approach. The most effective exercise
for 6 months. Since it is suggested that nitric oxide in low used to counteract loss of bone mass and strength seems to
concentrations might induce an increase in bone formation be any form of resistive exercise or combinations of
it may be one of those rare compounds that could activate resistive with other forms of exercise. Shackelford et al.
osteoblasts and thereby counteract the reduction in BMD (2004) used a horizontal exercise machine (HEM) devel-
during bed rest or spaceflight. oped by NASA to provide an intense resistive exercise
Testosterone levels decrease during bed rest (Vernikos regime. Subjects (resistive exercise: 5 men, 4 women;
et al. 1993) as well as spaceflight (Strollo et al. 1998). This control: 13 men, 5 women) performed 6 days a week of
could contribute to the catabolic state seen in microgravity. exercise during a 17-week horizontal bed rest study. The
It may be possible to counteract this catabolic state with changes of aBMD in specific sites of the exercising group
testosterone to improve muscle strength and thereby the compared to the control were as follows: lumbar spine,
mechanical loading on bone. During a 28-day head-down +3% vs. –1%; total hip, +1% vs. –3%; calcaneus, +1% vs.
tilt bed rest study testosterone enanthate was administered –9%; pelvis, -0.5% vs. –3%; total body, 0% vs. –1% The
by i.m. injection (200 mg/week) (Zachwieja et al. 1999). authors concluded that under their specific study conditions
Although protein balance was preserved in the group with controlled nutrient intake this resistive exercise re-
receiving testosterone injections, muscle strength was de- gime protected the loss of bone mass during bed rest.

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Equally good results were obtained in the Berlin bed rest et al. 2000; Heer et al. 2001a; b; Blanc et al. 2000). It is
study, which investigated the effects of combined resistive widely known that BMD and body mass index (BMI) are
and vibration exercise during 56 days of bed rest (Rittweger very closely correlated (Baker et al. 2000; Lennkh et al.
et al. 2006; Rittweger and Felsenberg 2004). As there was 1999). For example, the BMI of patients with anorexia
no group in this study that performed either vibration nervosa (AN) is a very good predictor of bone mineral
exercise or resistive exercise, the results of this study do not density in these patients (Hotta et al. 1998; Goebel et al.
provide information as to the differential effects of the two 1999). In contrast, weight gain of patients with AN re-
exercise regimes. What is remarkable however, is that verses bone resorption very rapidly (Caillot-Augusseau
maintencance of BMC in the lower leg was possible with et al. 2000a; Stefanis et al. 1998; Heer et al. 2002). As in
only about 10 min net exercise time per day. adolescent patients with AN, weight loss in postmeno-
Another form of resistive exercise makes use of a pausal women or energy intake reduction in exercising
gravity-independent ergometer, the so-called flywheel women is accompanied by bone mobilization, lowering of
(Alkner and Tesch 2004a, b). Its efficacy to prevent bone BMD, and osteoporotic fractures (Ricci et al. 1998; Ihle
loss and muscle atrophy was tested in a 90-day bed rest and Loucks 2004). Changes in bone turnover are also seen
study in 18 healthy young men (Alkner and Tesch 2004a). in athletes with inadequate energy intake (Thompson
Training sessions lasted about 45 min and were scheduled 1998). In male rowers a decrease in bone formation
every 2–3 days. Both for the hip and for the distal tibia, markers was seen after only 24 h of fasting (Talbott and
bone losses were about half as large in the exercise group Shapses 1998). Ihle and Loucks (2004) studied the dose–
as compared to the control group, suggesting a 50% effi- response relationship of decreasing energy intake on bone
cacy of this approach (Watanabe et al. 2004a). BMC turnover markers in young, habitually sedentary women.
measured in the tibia (4% level, mainly trabecular bone) They found that a diet that reduced total energy availability
14 days after the completion of bed rest was decreased less by about 80% led to a 29% significant increase in bone
in the flywheel group (–2.8% ± 2.3) than in the control resorption markers while the formation marker procolla-
group (–6.0% ± 5%; Rittweger et al. 2005). gen-i-c-terminal peptide (PICP) decreased significantly by
It has been proposed in several publications that fluid 10% when energy availability was reduced to 67%. The
redistribution as a result of bed rest and the resulting question therefore remains whether a combination of lower
reduction in fluid shear stress might contribute to the mechanical load such as bed rest together with reduced
changes in BMD in bones that are usually mechanically dietary energy availability would exacerbate the effect on
loaded in the ambulatory state (Klein-Nulend et al. 2003; bone turnover. Heer et al. (2004b) using a randomized
McGarry et al. 2005; Burger et al. 2003). This has led to crossover design in a two week HDBR-study found that
the hypothesis that lower body negative pressure (LBNP) reducing energy availability to 75% solely by decreasing
used to provide mechanical loading—ideally applied to- fat intake did not further increase bone loss as measured by
gether with some form of exercise—may be useful in bone resorption and formation markers. Apart from this
protecting bone loss during bed rest. This was put to the study where only fat intake was reduced, energy deficiency
test in a 30-day bed rest study in eight pairs of identical has usually been combined with decreases in all the other
twins (Smith et al. 2003). In the supine position, the nutrients. This is done by reducing total food intake rather
exercising twin ran 6 days/week on a treadmill within an than that of a single nutrient. The increase in bone
LBNP chamber for 40 min each day, with 5 min of static resorption markers or decrease in bone formation markers
LBNP at the conclusion of each run. Measuring the found in such studies where the total food content is re-
excretion of N-telopeptide (NTX) as a marker of bone duced is therefore caused by general malnutrition and
resorption, it was found that this form of training mitigated cannot be attributed to the deficiency of a single macro- or
the increase in bone resorption as compared to the control micronutrient.
group. On days 26/27 of bed rest, NTX-excretion was in-
creased by 59% in the non-exercising control group, Protein
whereas it was increased by only 32% in the LBNP plus
exercise group (Smith et al. 2003). Bed rest decreases muscle strength and muscle volume
(Zange et al. 1997; Berg et al. 1993; Rittweger et al. 2005).
Nutritional aspects This lower muscle mass is mainly caused by decreasing
protein synthesis rather than increased breakdown (Ferr-
Caloric intake ando et al. 1996; Biolo et al. 2004a, b) leading to a negative
nitrogen balance (Scheld et al. 2001). Increasing either
Food consumption is voluntarily reduced in astronauts in protein intake by supplementing branched chain amino
spaceflight resulting in the loss in body mass (Bourland acids or amino acids together with carbohydrate supple-

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mentation has been shown to overcome the protein loss duced (Smith et al. 1999; Zittermann et al. 2000) and
caused by inactivity (Stein et al. 2003; Paddon-Jones et al. calcitriol concentrations are decreased (Heer et al. 1999) so
2004). To determine whether increasing protein intake per that increased calcium intake above the recommended level
se counteracts reduced protein synthesis is currently being will not be absorbed. In short-term 6- and 14-day HDBR
tested by Biolo G. et al. (personal communication) in a studies it was shown that bone turnover was unchanged by
long-term bed rest study called WISE-2005. There are increasing calcium intake from 1,000 to 2,000 mg/day
opposing views on the effect of increased protein intake on (Heer et al. 2004a). Increasing calcium and vitamin D in-
bone turnover. Studies suggest that the elderly benefit from take above the recommended levels appear to be ineffec-
increased protein intake as evidenced by higher BMD and tive as a nutritional countermeasure to maintain bone mass
lower bone resorption marker levels (Ginty 2003; Dawson- in bed rest.
Hughes et al. 2004; Devine et al. 2005). Others argue that
increasing protein intake, especially in the form of the acid Sodium
forming amino acids, might raise bone turnover and de-
crease bone mass (Nordin et al. 1998; Reddy et al. 2002). It has been shown in several studies in pre- and postmen-
Based on this, Zwart et al. (2004) examined the relation- opausal women (Nordin et al. 1993) and calcium stone
ship between potassium intake and animal protein in a bed forming patients (Martini et al. 2000) that increasing so-
rest study in twins. They found that bone resorption was dium intake leads to a profound increase in calcium
reduced during high animal protein intake if the potassium excretion (Nordin et al. 1993) associated with lower aBMD
intake was high. High intake of animal protein increases (Martini et al. 2000). Nordin et al. (1993) postulated that
blood pH because of its high content of sulfur-containing the rise in urinary calcium excretion is sodium driven. Each
amino acids. Increased pH is a prerequisite for activating 100 mmol (2,300 mg) increase in sodium intake raises
osteoclasts to resorb bone (Arnett and Dempster 1986; urinary calcium excretion by 1 mmol (40 mg). Taking into
Krieger et al. 1992). Intake of potassium bicarbonate can account that the average calcium excretion is around 120 to
counteract the decreased pH, reduce osteoclast activity and 160 mg per day, the rise in calcium excretion by higher salt
thereby has profound beneficial effects on bone minerali- intake is substantial. These findings were supported by
zation even in immobilization (Fettman 2000). Arnaud et al. (2000) in a 7-day bed rest study. The
mechanism by which high sodium intake exacerbates uri-
Calcium and vitamin D nary calcium excretion is not fully understood. Heer et al.
(2000) have shown that high salt intake leads to sodium
Adequate calcium intake is a prerequisite to mineralize storage without concomitant fluid retention. The same
bone during life. Convincing evidence has emerged with group has further examined the effects of high salt intake
respect to the effects of dietary calcium intake on bone on acid-base balance in a metabolic ward study (Frings
health in all age groups. A number of reports led to a et al. 2005). They demonstrated that increasing salt intake
consensus view on the effectiveness of calcium together leads to decreased serum pH, bicarbonate and base excess
with vitamin D supplementation in postmenopausal oste- levels. Even mild metabolic acidosis (pH-changes of
oporosis (Chee et al. 2003; Lau and Woo 1998; Cumming < 0.05) may activate osteoclasts and may cause apprecia-
and Nevitt 1997; Ilich and Kerstetter 2000; Prentice 2004). ble bone loss over time in ambulatory conditions (Arnett
High calcium intake cannot prevent bone loss but can re- 2003) and may exacerbate bone loss in bed rest.
duce the rate of bone loss in older women.
Dawson-Hughes et al. (1997) showed that combined Vitamin K
supplementation with calcium and vitamin D for 3 years
significantly reduced non-vertebral fracture rates in men Vitamin K is involved in the post-translational formation of
and women (mean age 71 years). gamma-carboxyglutamate (GLA) residues in proteins. For
Astronauts in space have a low calcium and vitamin D osteocalcin this means that full carboxylation is mandatory
intake (Smith et al. 2005) together with high serum calcium in order to fulfill the full function of osteocalcin in bone.
levels because of increased bone resorption. High serum Bone contains at least three GLA-proteins: osteocalcin,
calcium concentration and low 25-hydroxyvitamin D levels matrix-GLA Protein, and protein S (Hauschka et al. 1989;
are found in astronauts (Smith et al. 2001) as well as during Vermeer et al. 1995). Vitamin K may also have a second
bed rest (van der Wiel et al. 1991). One might argue that function, in inhibiting osteoclast activity and bone resorp-
increasing calcium intake and vitamin D supplementation tion (Hara et al. 1995; Kameda et al. 1996). A number of
might counteract the microgravity-related and bed rest-in- clinical trials have shown that increased vitamin K intake
duced bone losses. However, data from the MIR 97 mission leads to an increase in circulating bone formation markers
and bed rest studies show that calcium absorption is re- and a reduction of urinary bone resorption markers (Kna-

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pen et al. 1989, 1993). In women low vitamin K intake is ning in space or experiments were poorly designed—
associated with a lower BMD and increased risk of hip inadequate pre-flight control and post-flight recovery
fractures (Booth et al. 2000, 2003). Supplementing the diet data—or, other variables confused the outcome. For in-
of postmenopausal women with vitamin K1 (phyllochi- stance the light intensity inside the spacecraft may have
none, 1 mg/day) over 3 years led to a significant increase been too low to maintain clean and regular light/dark
in BMD in the femoral neck (Braam et al. 2003). During synchronizing cues and the 90 min day/night cycles
the 179 day Euromir 95 mission supplementation with experienced in low Earth orbit (LEO) further adds to the
10 mg Vitamin K was tested as a countermeasure during confusion.
the second part of the mission and showed promising re- Nevertheless, disturbed rhythms have been recorded in
sults (Vermeer et al. 1998; Caillot-Augusseau et al. 2000b). specimens from beetles to rats. Astronauts have com-
Bone formation markers were decreased in the first part of plained enough to request preflight bright light treatment to
the mission without Vitamin K supplementation, whereas synchronize their rhythms to those of their landing site.
in the latter part of the mission when Vitamin K supple- The single long-term monitoring of the oral body temper-
mentation was provided serum bone alkaline phosphatase ature and alertness rhythms exists of one astronaut (JL)
(bAP) levels were comparable to those preflight. However, who spent four months on the Russian space station Mir
vitamin K did not affect bone resorption as shown by the (Monk et al. 2001). This study provided more reliable data
excretion of a bone resorption marker (Vermeer et al. 1998; of the gradual reduction in rhythm amplitude to the point
Caillot-Augusseau et al. 2000b). where these rhythms practically disappeared. JL’s endog-
Further studies using Vitamin K supplementation in enous clock seemed to function quite well throughout his
space and bed rest should confirm whether such dietary first 90 days in space. Thereafter (days 110–120,) his
countermeasures may be effective in counteracting bone rhythms of body temperature and alertness were consid-
loss in disuse osteoporosis as well. erably weaker with consequent reduction in sleep.
In summary, resistive exercise combined with vibration Although several horizontal bed rest studies had re-
exercise might be a very promising countermeasure which corded changes in body temperature (BT) and heart rate
is able to keep up bone mass with only a rather short (HR) rhythms as well as those of hormones such as cir-
training period per day. However, these may be even more culating insulin and cortisol, no such studies appear to have
effective when combined with anabolic nutrients such as been reported since 1986 (Sandler and Vernikos 1986).
vitamin K or anabolic pharmaceutical agents like nitric These earlier observations showed that rhythmicity was
oxide or PTH. Further studies are mandatory in order to maintained for the first 20 days of bed rest. Thereafter, a
evaluate reliably optimal countermeasure combinations for shift in the daily peak of BT and HR and a reduction in the
astronauts on a long-term mission to Mars or any person amplitude were seen. Over the 56 days of horizontal bed
immobilized for different reasons. rest circulating hormones sampled every 4 h for 48 h
periods also showed shifting of the peak and a reduction in
amplitude. The insulin peak appeared no longer tied to
Rhythms, sleep, mood and cognition meal times, occasionally occurring in the middle of the
night. One HDBR study followed salivary cortisol over
Biological Rhythms, sleep, feeling good and performing 7 days and found a similar reduction in the amplitude of
well form the basis of daily activity and well-being in life the rhythm as well as a progressive reduction in the mean
on Earth. Jet lag and night-shift work bring on conse- daily cortisol level during the bed rest (Vernikos J. and
quences of disturbed sleep, not feeling at one’s best and has Keil L. C., unpublished observations).
well-documented consequences on both health and per- Continuous bed rest is a form of sensory deprivation. It
formance. eliminates the regular daily alteration between activity and
rest and reduces the number of variations in the pull of
Biological rhythms gravity on the body associated with changes in posture. The
stability of circadian rhythms deteriorates in healthy young
From the beginning of the space era, circadian rhythm bed rest volunteers even when the brain is provided with such
experts predicted disturbances in these rhythms when liv- other cues as regular mealtimes, exercise in the horizontal
ing organisms would be removed from Earth’s gravita- position and regular changes in light and darkness. Body
tional pull. Experiments to resolve the role of gravity on rhythms begin to lose their synchronization after as little as
the biological clock have not been without their problems ten days of bed rest and the disruption reaches its height after
and the question remains unequivocally unanswered. This 22–24 days. It is most likely that under normal living con-
has been either because flights have been too short to ditions light/dark cycles and gravity work together to rein-
establish whether circadian rhythms are indeed free-run- force the signal needed to synchronize body rhythms.

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Though no further work on rhythms has been done in the of game autonomously contributes to the positive effects
past 20 years of bed-rest studies, this is one of the areas on the mental health of the volunteers (Ishizaki et al.
that present a gap in our knowledge and where it would 2004). Pavy-Le Traon et al. (1994) investigated the cog-
appear that this simulation model, especially with longer nitive, perceptive and motor abilities of male volunteers
duration studies, should yield data important of both fun- by a battery of standardized and computerized tests in a
damental and operational importance. 28-day HDBR. No downgrading of psychomotor perfor-
mance was observed. By studying performance and mood
Sleep scales during a 30-day BR with and without exercise,
DeRoshia and Greenleaf (2003) concluded that mood and
Cycles of sleep and wakefulness are the most obvious of performance did not deteriorate in response to prolonged
the physiological daily rhythms. Upset rhythms lead to BR and were not altered by exercise training. However,
disturbed sleep. Disturbed sleep has been a common they considered that the decline in activation mood scales
complaint among astronauts and cosmonauts. On short in the exercise group may reflect overtraining or excess
missions they tend to sleep fewer hours because their work- total workload in this group. This point of possible psy-
load tends to be heavier. Monitoring of sleep has been chological consequences of ‘‘over occupation’’ or ‘‘over-
remarkably normal yet astronauts complain that they do not testing’’ has to be considered in the design of the HDBR
wake up feeling refreshed (Dijk et al. 2001). After they experiments.
return to Earth astronauts have complained of nocturnal In summary, several early horizontal bed rest studies
diuresis that interferes with their ability to have a good showed changes in body temperature, heart rate and hor-
night’s sleep (personal communication). mone rhythms. However results in this field are scarce. No
Head-down bed rest subjects also complain of disturbed systematic sleep monitoring has been carried out. No
sleep. Disturbed BT rhythms could also affect sleep. Nor- downgrading of psychomotor performance was observed
mally BT peaks in the afternoon, 1 h later than the time of but only few studies have dealt with mood and cognitive
maximum HR in men but at the same time in women. aspects of bed rest.
Sleepiness is triggered by, among other factors, a drop in
temperature late at night, but during long-term bed rest BT
may still be relatively high at the time the volunteers Artificial gravity
should be falling asleep.
Remarkably, no systematic sleep monitoring has been Artificial gravity represents an alternative approach to
carried out during bed rest studies. prevent the effects of weightlessness. It acts on all physi-
ological systems simultaneously. Different countermea-
Mood and cognition sures already described like exercise and/or LBNP have
beneficial but partial effects on different physiological
Everybody knows that psychological aspects (psycholog- systems. For example, the most effective exercise used to
ical selection, psychological support, leisure time organi- counteract loss of bone mass and strength seems to be any
sation, communications ….) are essential to conduct form of resistive exercise but its effect on orthostatic
HDBR experiments in particular long duration ones. But intolerance is limited. Artificial gravity will potentially
only few studies have been dealing with mood and cog- mitigate bone loss, cardiovascular de-conditioning, muscle
nitive aspects of bed rest. Ishizaki et al. performed several atrophy, and neuro-vestibular disturbances. However, the
studies on psychological aspects. They found a tendency requirements for use of artificial gravity as a countermea-
to development of depression and neuroses after a 20-day sure have yet to be defined (review, Clement and Pavy-Le
BR (six males, three females). The urinary excretion of Traon 2004). Artificial gravity can be accomplished either
17-hydroxycorticosteroid used as an indicator of stress did by rotating the entire space vehicle, or by using an on-
not vary significantly (Ishizaki et al. 1994). In a second board centrifuge. In both cases, the level of artificial
20-day BR experiment (5 males, 5 females), they also gravity is dependent upon the angular velocity and the
reported a tendency to development of depression and square of the radius about which the rotation is executed.
neuroses with an increase in urinary excretion of 17-hy- However, a rotating spacecraft presents complex design,
droxycorticosteroid (Ishizaki et al. 1997, 2002). More re- financial, and operational challenges, particularly for a
cently, they entrusted the participants (male) to a 20-day maneuvering station. From a practical standpoint, astro-
HDBR to manage their leisure time; the volunteers at- nauts will probably not need gravity 24 h a day to remain
tended a game in which all of them could take part over healthy. Therefore, an on-board short-arm centrifuge may
the experiment period. By comparison with previous be a more realistic means to provide the required artificial
experiments, the authors consider that the implementation gravity environment (Burton 1997; Burton and Meeker

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1992; review, Clément and Pavy-Le Traon 2004; Vil-Vil- The results obtained by Hastreiter and Young (1997)
liams et al. 2001) (Fig. 12). could also be helpful to define the SAC protocols. These
Centrifugation-like protocols (e.g., standing and LBNP) authors investigated, on a 2-m radius centrifuge, the effects
were also used as a way to maintain orthostatic tolerance of different acceleration levels (ranging from 0.5 to 1.5 g at
and exercise capacity. Only few studies have evaluated the the feet) for 1 h on cardiovascular responses. They con-
effects of the short arm centrifugation in bed rest (see re- cluded that 1.5 g at the feet was similar to standing, but
view, Clement and Pavy-Le Traon 2004). that 0.5 g at the feet failed to produce significant effects.

Centrifugation-like protocols Lower body negative pressure and exercise

Effect of standing or walking Lower body negative pressure (LBNP), like standing, in-
duces a shift of fluid from the upper to the lower part of the
To study the role of intermittent passive (standing) and body. The effects of LBNP and/or exercise on the different
active (walking) g-exposure as a countermeasure during systems, cardiovascular and musculo-skeletal ones in par-
HDBR, Vernikos et al. (1996) performed a series of five 4- ticular, have been detailed in the respective chapters. The
day experiments on the same nine male volunteers. bed rest experiments have confirmed the advantage of
Orthostatic tolerance during a 30-min 60 head-up tilt test combining LBNP with other countermeasures, in particular
and maximal oxygen uptake were assessed before and after muscular exercise. LBNP and muscular exercise have
the HDBR study. The subjects were instructed to walk or probably a combined action on plasma volume. LBNP
stand for a total of 2 or 4 h per day in 15 min increments combined with treadmill exercise in supine subjects pro-
hourly or to remain in HDBR (control). The main con- vides both cardiovascular and musculo-skeletal stimulation
clusions are: (a) standing completely (4 h) or partially (2 h) (Murthy et al. 1994; Lee et al. 1997; Watenpaugh et al.
prevented the post HDBR orthostatic intolerance; (b) 2000; Smith et al. 2003).
walking (2 and 4 h) and standing (4 h) attenuated the de-
crease in peak oxygen uptake; (c) standing (4 h) and Short-arm centrifugation during bed rest studies
walking (4 h) attenuated plasma volume loss; and (d)
walking (2 and 4 h) attenuated the increase in urinary In a short-arm centrifuge, the subject is lying on his/her
calcium excretion. These results can be helpful to define back with the head towards the centre; the centrifugal force
the short arm centrifugation (SAC) protocols to be applied (+Gz) is directed head-to-foot. White et al. (1965, 1966)
in HDBR. The authors also point out that in addition to performed the first experiments with short-arm centrifu-
their duration, the number of exposures to postural stimuli gation during horizontal bed rest. A 1.25-m radius centri-
may be an important factor (Vernikos et al. 1996; Vernikos fuge that provided 1 to 4 g at the feet along the body z-axis
1997). was employed. In a 10-day bed rest a modal regimen of
1.75 g (heart level) four times daily (20 min per exposure)
prevented the post bed rest orthostatic intolerance assessed
by a 20-min head-up tilt (White et al. 1966).
Japanese investigators performed recently several four-
day HDBR studies using 2-g centrifugation for 60 min
daily in a 1.8-m short-arm centrifuge (Iwasaki et al. 1998,
2001; Sasaki et al. 1999; Yajima et al. 1994, 2000). They
compared the cardiovascular responses (plasma volume,
heart rate variability, baroreflex sensitivity, maximal oxy-
gen consumption) of volunteers exposed to 2 g for 30 min
twice daily to controls. The authors concluded that the
daily 60-min exposure to 2 g counteracted the changes in
autonomic cardiovascular control; partly reversed hypo-
volemia induced by HDBR, but could not prevent the de-
crease in exercise capacity (Iwasaki et al. 2001).
Few studies have investigated the effect of artificial
gravity on muscle in humans. Akima et al. (2005) recently
showed that intensive cycle training (to 90% of maximum
HR) with short-arm centrifuge-induced artificial gravity on
Fig. 12 Example of a short arm centrifuge (NASA) alternate days during a 20-day bed rest maintained the size

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and function of thigh skeletal muscles (MRI, EMG, force generate an acceleration vector mimicking gravity (di
assessment). Prampero 1994; di Prampero and Narici 2003).
However, several questions associated with the use of
artificial gravity as a credible countermeasure remain. In
particular, what level of gravity is needed? Is a fraction of Concluding remarks
Earth’s gravity level (1-g) sufficient? How long must the
centrifugation be applied per session? How many times per The review of bed rest studies conducted in the past
day should centrifugation be employed? How would the 20 years has provided a sound foundation by adding to the
centrifugation be applied with respect to the flight schedule knowledge base and developing tools to enable humans to
and return to Earth? What are the constraints? live, work, travel and some day explore other planets.
What are the benefits of using centrifugation in combi- There is no doubt that HDBR has proven its usefulness as a
nation with other countermeasures? Some studies per- reliable simulation model. The inclusion of women vol-
formed with SAC during dry immersion have indicated unteers as test subjects although insufficient, is well on the
potential value-added by combining centrifugation with way to correcting the gap in documenting and under-
exercise and a water and salt supplement (Shulzhenko and standing gender differences in physiology in general.
Vil-Viliams 1992; Vil-Viliams 1994; Vil-Viliams and Bed rest studies are particularly valuable at times when
Shulzhenko 1980). Combining centrifugation with exercise access to space is severely limited. There has therefore
will also contribute to reducing muscle atrophy and bone been a proliferation, on an international scale, in the
changes. number of studies conducted since the literature was last
A Human Powered Centrifuge (HPC) (Fig. 13) was reviewed in 1986. Longer durations, more international
developed at NASA-Ames as a research tool to provide cooperation and a more concerted effort to identify and to
exercise and gravitational forces simultaneously using only evaluate effective countermeasures have characterized this
human effort (Greenleaf et al. 1996, 1999). Cardiovascular period. The fascination with the role of gravity in physi-
responses with passive acceleration or combined with ology has become contagious. The greater emphasis on
exercise were evaluated with this centrifuge (Chou et al. integrative rather than systems approaches and the coming
1998; Greenleaf et al. 1996, 1999). The authors concluded together of multidisciplinary, multinational teams to solve
that in non-bedrested subjects, addition of + 2.2 Gz problems have all been necessary and desirable conse-
acceleration does not significantly influence levels of quences.
oxygen uptake, heart rate, or pulmonary ventilation during Clinical and social benefits have also resulted. The
sub-maximal or maximal cycle ergometer l-g exercise on a benefit in knowledge, technologies and applications that
short-arm centrifuge. have resulted from space-related biomedical research is
Other systems have been proposed but not tested, like myriad. The ability to go into space in microgravity, has
the twin bikes system (aimed at reducing cardiovascular allowed us to explore how the force of gravity has shaped
and muscular deconditioning) in which cyclists moving the evolution and physiology of life on Earth. But we have
along the inner wall of a cylindrically shaped module barely started this exploration.
With the advent of spaceflight healthy, young men and
women were made less healthy by lying in bed. The
ground-based research using bed rest as the simulation
model for microgravity, results in the same changes in
human physiology, though the rate of change is slower and
less marked than in space. We now know that in the virtual
absence of gravity in space, in the reduced influence of
gravity in bed rest and in the decreasing use of gravity
throughout adult life, similar changes result. In the first two
cases they are reversible. We call the last of these aging
and presume they are irreversible. We may also see similar
changes during development as life even for the young
becomes more sedentary.
The value of the bed rest model lies in reducing the
effectiveness of gravity’s influence on the body. Like
space, it telescopes in healthy, young individuals what
happens to all on Earth over many, many years. It allows
Fig. 13 The human powered centrifuge (NASA) over a very short period of time the study of the develop-

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ment and progression of these changes that may at some Appendix continued
time become irreversible disorders. ECV Extra-cellular volume
The development of countermeasures for the purpose of ECW Extra-cellular water
protecting spaceflight crews from these undesirable effects EEG Electroencephalography
should be directly relevant to protecting those living on EF (Cardiac) ejection fraction
Earth from developing similar changes. More immediately, EMG Electromyography
bed rest data are directly applicable to accelerate recovery
EPO Erythropoetin
and rehabilitation from a variety of injuries, surgery, dis-
FW Flywheel ergometer
ease and hospitalisation.
G Earth’s gravity
As the value of bed rest as a simulation model for
GABA Gamma aminobutyric acid
inducing the effects of spaceflight has gained acceptance,
GLA Gamma-carboxyglutamate
an increasing number of bed rest studies are being con-
GLUT Glucose transporter protein
ducted in a variety of institutions throughout the world.
Gx Gravitational force acting on a human from chest to back
Furthermore, bed rest studies are being used in research as
Gz Gravitational force acting on a human from head to feet
a tool in understanding human physiology and in clinical
HDBR Head-down bed rest
and nursing research as well. Clinical practice may have
HF High frequency power
arrived at that conclusion eventually. But without the bed
HR Heart rate
rest studies in healthy human volunteers initiated because
of the Space Age, it would not have come about as rapidly. HU Hindlimb unloading
Now, the intensive effort to develop specific countermea- HUT Head-up tilt
sures to accelerate rehabilitation of crews on exploration IAM Institute for Aerospace Medicine (DLR, Cologne,
Germany)
missions could find clinical applications in preventing
ICW Intra-cellular water
inactivity- or other gravity-related disorders of today or
IKE Intermittent resistive isokinetic exercise
treating the sick, the injured and the disabled here on Earth.
IL Interleukin
ISS International space station
ITE Isotonic cycle ergometer exercise
Appendix: Acronyms
LBNP Lower body negative pressure
LEO Low earth orbit
LVDV Left ventricular end-diastolic volume
MCA Middle cerebral artery
ABP Arterial blood pressure
MEDES Institute for Space Medicine and Physiology (Toulouse,
ACTH Adrenocorticotropic hormone France)
ANP Atrial natriuretic peptide MHC Myosin heavy chain
ARC Ames Research Center (NASA) MLC Myosin light chain
AVP Arginine vasopressin MRI Magnetic resonance imaging
BAP Bone alkaline phosphatase MSNA Muscle sympathetic nerve activity
BFV Blood flow velocity MTWA Microvolt T-wave alternans
BIS Bioelectrical impedance spectroscopy MVC Maximum voluntary contraction
BMC Bone mineral content NASA National Aeronautics and Space Administration (of the
BMD Bone mineral density USA)
BMI Body mass index NASDA National Space Development Agency (of Japan, now
BP Blood pressure JAXA)
BR Bed rest NO Nitric oxide
BT Body temperature NOS Nitric oxide synthase
CNES Centre National d’Études Spatiales (French Space Agency) OGTT Oral glucose tolerance test
CSA Cross-sectional area OI Orthostatic intolerance
CVR Cerebro-vascular resistance PCSA Physiological cross-sectional area
DEXA Dual energy X-ray absorptiometry PICP Procollagen-I-C-terminal peptide
DLR Deutsches Zentrum für Luft und Raumfahrt (German pQCT Peripheral quantitative computer tomography
Aerospace Centre) PRA Plasma renin activity
ECG Electrocardiogram PTH Parathyroid hormone

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Appendix continued Alkner BA, Tesch PA (2004b) Knee extensor and plantar flexor
muscle size and function following 90 days of bed rest with or
PV Plasma volume without resistance exercise. Eur J Appl Physiol 93:294–305
QCT Quantitative computer tomography Alonso A, Fernandez Y, Fernandez R, Ordonez P, Moreno M, Diaz F,
QUS Quantitative ultrasound Patterson AM, Gonzalez C (2005) Effect of food restriction on
the insulin signalling pathway in rat skeletal muscle and adipose
RCM Red cell mass
tissue. J Nutr Biochem 16(10):602–609
SERM Selective estrogen receptor modulator Andersen JL, Gruschy-Knudsen T, Sandri C, Larsson L, Schiaffino S
SOL Soleus muscle (1999) Bed rest increases the amount of mismatched fibers in
SV (Cardiac) stroke volume human skeletal muscle. J Appl Physiol 86:455–460
Arbeille P, Gauquelin G, Pottier JM, Pourcelot L, Guell A, Gharib C
TBW Total body water (1992) Results of a 4-week head-down tilt with and without
TLC Total lung capacity LBNP countermeasure: II. Cardiac and peripheral hemodynam-
TNF Tumor necrosis factor ics comparison with a 25-day spaceflight. Aviat Space Environ
Med 63:9–13
TPR Total peripheral resistance
Arbeille P, Fomina G, Roumy J, Alferova I, Tobal N, Herault S
TSH Thyroid-stimulating hormone (2001) Adaptation of the left heart, cerebral and femoral arteries,
VBMC Volumetric bone mineral content and jugular and femoral veins during short-and long-term head-
VL Vastus lateralis muscle down tilt and spaceflights. Eur J Appl Physiol 86:157–168
Arbeille P, Sigaudo D, Pavy Le Traon A, Herault S, Porcher M,
VO2peak Peak aerobic exercise capacity Gharib C (1998) Femoral to cerebral arterial blood flow
VO2max Maximum oxygen uptake during exercise redistribution and femoral vein distension during orthostatic
WISE- Women International Space Simulation for Exploration tests after 4 days in the head-down tilt position or confinement.
2005 2005 Eur J Appl Physiol Occup Physiol 78:208–218
Arnaud SB, Morey-Holton E (1990) Gravity, calcium, and bone:
Update 1989. Physiologist 33:S65–S68
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Acknowledgements This review is based on many excellent re- urinary calcium excretion in a human bed rest spaceflight model.
search studies carried out over the last 20 years. Scientists who per- Aviat Space Environ Med 71:1115–1119
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