Mecanismos de fatiga

Dr. Jorge Cancino L. PhD.

Avda. Pedro de Valdivia 1509
Providencia, Santiago
+56 2 2420 7100
www.finisterrae.cl
Aguda: Es causada por un agente identificable, autolimitada, ocurre en sujetos sanos y
desaparece con el descanso adecuado.

Crónica: Es la que acompaña a las enfermedades con duraciones de más de 6 meses.

Sus causas son multifactoriales y generalmente no desaparece con el descanso y no se
relaciona con el esfuerzo físico.
 Tipos de Fatiga
según duración

• Fatiga de corto plazo.

 Tipos de Fatiga
según duración
• Fatiga de plazo
intermedio.
 Tipos de Fatiga
según duración

• Fatiga de largo plazo.

Tipos de Fatiga según orígen

Fatiga Neural
o central

Fatiga Metabólica
o periférica
Fatiga Central

Fatiga Neural
o central
Con la fatiga se reduce el drive
de motoreuronas, indicando una
perturbación central.
SEROTONINA
Albúmina
Albúmina
AGL
Trp Albúmina

Trp
BCCA
Trp
BCCA

Trp

Trp Neurona
5-HT

Reposo
Modificado de J.D. Fernstrom, en Davis, J.M. and Bayley, S., Med Sci Sports
Exerc., (29) N°1, pp. 45-57, 1997).
 Albúmina
Albúmina
AGL
AGL Albúmina

Trp Albúmina
BCCA AGL
Trp Trp
Trp
Trp

5-HT
Trp Neurona
5-HT

5-HT

Ejercicio
Modificado de J.D. Fernstrom, en Davis, J.M. and Bayley, S., Med Sci Sports
Exerc., (29) N°1, pp. 45-57, 1997).
 El cerebro aumenta la captación
de triptofano cuando el ejercicio es
prolongado y no va acompañado
de carbohidratos
 Fatiga Periférica

Fatiga Metabólica
o periférica

Generalmente ocurre por depleción de sustratos o acumulación de metabolitos

Lactato
8 horas 15 minutos y 15 segundos!!!!
George Hood
Daniel Scali
Motivación y fatiga
 FIG. 1. Early studies of maximal voluntary activation and central fatigue. A: data ob
ergograph. Trace indicates the distance moved by the middle finger when lifting a weight
tracing” and one obtained 24 h later “after lecturing” are shown. [Redrawn from Mosso
a maximal voluntary contraction (MVC) of finger flexion and force produced by stimula
elbow (stimulus rate not specified) under isometric conditions. Artificial stimulation pro
voluntary effort,” although this is not clear in all the records (see horizontal dashed line)
weights could be lifted by artificial electrical stimulation and not volition (see Fig. 4).

from clinical cases, that muscles would be torn, tendons maximal c

Estímulos centrales ruptured, and bones broken. [We now know that unless kept in bo
there has been a pathological change in the tendon or activate t
bone, the strength of bone and tendon exceeds that of prompted
muscles (775).] Thus the common view was that the Merton (5
stimulatio
imal force
A pesar de evidenciarse la fatiga voluntary
a lo largo de la duración de la ficial” stim
synchrono
prueba, cada vez que se aplicaba difference
un estímulo sonoro de magnitud the stimu
el rendimiento muscular mejoraba. maximal t
Does
lation exc
reports cla
the errors
and are no
(1928) had
records su
match the
Gandevia, S. C. Spinal and Supraspinal Factors in Human Muscle Fatigue.
special m
FIG.
Physiol Rev 81: 1725–1789, 2001
2. Classical study of factors affecting maximal voluntary produced
strength. Mean value for brief MVCs of elbow flexors made at 1-min pared the
intervals by 10 subjects. Control contractions (open circles), contrac- above the
tions preceded by an unexpected gunshot (solid circles), and a final
contraction (star) in which the subject shouted are shown. [Redrawn tion. Diffic
from Ikai and Steinhaus (354).] alter the
 Ergorreceptores

• Corresponden a terminaciones libres III y IV

• Terminaciones III mielinizadas y IV no mielinizadas

• Terminaciones III = Mecano receptores

• Terminaciones IV = Metabolo receptores.
Ergoreflejo

Definición: Es un sistema de retroalimentación cardiorrespiratorio que está

compuesto por el metaborreflejo (activado por la acumulación de metabolitos en el
músculo esquelético) y el mecanorreflejo (provocado por el estiramiento mecánico
de músculos y tendones). El resultado final consiste en un aumento de la ventilación,
aumento de las resistencias periféricas y del gasto cardíaco, lo que resulta en un
aumento de la presión arterial (PA) sistémica.

A. Aimo et al. (2021)

 Ergorreceptores y su
rol durante el ejercicio.

La acción muscular provoca un O2

aumento de aferentes desde los
ergoreceptores con el objetivo de ⍺
“solicitar” mayor disponibilidad
de oxígeno.
 Ergorreceptores y su
rol durante el ejercicio.

La exacerbación del ergoreflejo

provoca una respuesta inhibitoria Disnea
refleja, un incremento en la
percepción del esfuerzo asociado
⍺
a una mayor disnea e incremento
Fatiga
de la actividad simpática,
provocando una menor tolerancia
al ejercicio.
Ergoreceptores y su rol en la fatiga
 Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Autonomic Neuroscience: Basic and Clinical

journal homepage: www.elsevier.com/locate/autneu

Autonomic responses to exercise: Group III/IV muscle afferents

and fatigue☆
Markus Amann a,b,⁎, Simranjit K. Sidhu a, Joshua C. Weavil b, Tyler S. Mangum b, Massimo Venturelli c
a
Department of Medicine, University of Utah, Salt Lake City, UT, USA
b
Department of Exercise & Sport Science, University of Utah, Salt Lake City, UT, USA
2 c
Department M. Amann etSciences
of Biomedical al. / Autonomic Neuroscience:
for Health, University Basic
of Milan, Italy and Clinical xxx (2014) xxx–xxx

et al., 2011a). Peripheral fatigue was quantified via the pre- to post-
a r t i c l e i n f o a b exercise
s t r a cdecrease t Personas con insuficiencia cardiaca
in quadriceps twitch force evoked via supramaximal
M. Amann et al. / Autonomic Neuroscience: Basic and Clinical
Article history:
femoral nerve stimulation. Earlier studies utilizing an identical pharma-
Group III and IV muscle afferents originating in exercising limb muscle play a significant role in the development
Received 12 June 2014 cological approach to temporarily block group III/IV
of fatigue during exercise in humans. Feedback from these sensory neurons to the central nervous system (CNS) muscle afferents
Received in revised form 17 September 2014 haveincreases
reflexively documented ventilation thatand exercise
central (cardiac in the absence
output) of sensory
and peripheral feedback
(limb blood isflexors) not d
flow) hemodynamic
Accepted 13 October 2014
Available online xxxx
characterized
responses during exercise by substantial
and thereby assures hypoventilation
adequate muscleand blood an flow attenuated
and O2 delivery. exercise cent findings
This response de-
picts pressor
a key factorresponse
in minimizing the rate of decreased
including development of peripheral
central (i.e. fatigue
cardiac and inoutput)
optimizingand aerobic exercise
capacity. On the other hand, the central projection of group III/IV muscle afferents impairs performance and limits
III/IV muscle
Keywords: peripheral (leg blood flow) hemodynamic responses during exercisetense whole b
Neural feedback the exercising human via its diminishing effect on the output from spinal motoneurons which decreases volun-
(Amann
tary muscle et al.,
activation (i.e.2008, 2009,
facilitates central 2010,
fatigue). 2011a,
Accumulating 2011b; evidenceGagnon et al.,
from recent 2012).
animal studies suggests
Central fatigue Investigat
Exercise pressor reflex Consequently,
the existence of two subtypes when of groupconstant-load
III/IV muscle afferents. leg cycling While oneis performed
subtype only respondsin theto physiological
body exercise
Circulation absencelevels
and innocuous of locomotor
of endogenous muscle
intramuscularafferent feedback,
metabolites (lactate, leg ATP, blood
protons) flow and Owith
associated 2 ‘normal’,
Ventilation predominantly aerobic exercise, the other subtype only responds to higher and concurrently noxious levels of the ing from
delivery are markedly attenuated compared to the same exercise per-
metabolites present in muscle during ischemic contractions or following, for example, hypertonicSpecifically, saline infu- a
formed with an intact neural feedback mechanism. Given the critical
sions. This review discusses the mechanisms through which group III/IV muscle afferent feedback mediates
both role
centralof andblood
peripheral fatigue2indelivery
flow/O exercising humans. in theWe development
also briefly summarize of fatigue [seetate
the accumulating central fa
evidence
from above;
recent animal(Amann and humanand studies
Calbet, 2008)], the
documenting rate of of
the existence accumulation
two subtypes of of periph-
group tion to
III/IV muscle the pr
affer-
ents and
eralthe relevance
fatigue isofupthistodiscovery
60% faster to the during
interpretationexercise of previous with work and the design
impaired of future studies.
vs intact circulatory an
© 2014 Published by Elsevier B.V.
group III/IV muscle afferent feedback (Amann et al., 2011a; Sidhucilitating effe
et al., 2014). Taken together, by facilitating circulatory and ventilatorymuscle affere
responses, group III/IV muscle afferent feedback ensures adequate mus-
1. Introduction In order to assure a sufficient link to the original work in the pends
face ofona how
cle blood flow/O2 delivery during exercise and thereby prevents prema-
restricted number of references, we would be citing various
ture fatigue at the level of the locomotor muscle. This neural feedback
to circumven
other
Both whole body (e.g. cycling) and single joint (e.g. isometric/ review articles.
dynamic knee extension) exercise of sufficient duration mechanism and intensityplays an important role in optimizing fatigue resistancesingle leg kne
reduce the force/power generating capacity of muscles during physical
involved in theactivities in healthy humans.
followed by t
task. This exercise-induced decrease is determined The arterial
by a peripheral baroreflex
andmaximal 1.1. Group has been suggested
III/IVcontraction
muscle afferent to
feedback attenuate and the
exercise: central goal was to de
Fig. 1. Discharge frequency [impulses per 2 s; (Imp/2 s)] of group III (panel A) and group Fig.
IV2. Reduction
AUTNEU-01705; inofquadricep
No Pages 5 voluntary strength (MVC) induced viaSome basics
a central [i.e. related to the central nervous
(panel B) muscle afferents recorded from dorsal root before, during, and after locomotor
system effects
(CNS)] of group
component III/IV
9 min of constant-load single leg knee-extensor muscle afferents
exercise on the
(25/50/80% exercise pressor
of peak workload, response extensor exer
Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx
(Allen et al., 2008; Gandevia, 2001). ‘Peripheral 3 min fatigue’
each) viain encompasses
their
patients interaction
with chronic in With
heartthe the onset
nucleus
failure. The of exercise,
tractus
exercise was contraction-induced
solitarii
performed (Kim withet al.,
intact mechanical
2005; and and
thereby l
exercise evoked by electrical stimulation of the mesencephalic locomotor region in decere-
biochemical changes within the contracting muscle
Sheriff leading to an
et (fentanyl)
al., 1990; chemical
Waldrop stimuliand begin
Mitchell,to activate 1985). molecular In receptors
other words,located on the
brate cats. The horizontal bar denotes the exercise period. Note the immediate increase (control)
of and blocked neural feedback from the lower
Contents lists available at ScienceDirect
limb. From Amann et al. exercising co
attenuated
both group III and IV locomotor muscle afferent dischargeforce/power
at the onsetresponse to neural
of exercise excitation.
and(Amann
the al.,‘Central
etgroup fatigue’,
III/IV-mediated
2014). terminal
pressor endresponses
of both thinly to myelinated
exercise have (group III) and
been docu-unmyelinated
maintained response until the exercise is structurally
terminated. including the brain
From Adreani et al. and the spinal
(Adreani et al.,cord, refers to the decrease (group IV) nerve fibers with their receptive fields within skeletal ditional mus- contr
mented to be larger in the absence of the arterial baroreflex. Based on
1997). in force/power secondary to a reduction in descending motor drive and Autonomiccle. The Neuroscience:
exercise-induced Basic
activationand Clinical
of these receptors confounding
increases the
previous experiments in endurance exercising humans showing that at-
the efficacy of the afferent pathways which combined result in a de- spontaneous discharge of the thin fiber muscle afferents (Adreani
tively exercis
crease in the output from spinal motoneurons and tenuated
thus voluntary feedback
muscle j ofrom u et
r n aal.,
group
l h o1997;
III/IV
m e p a g eKaufman
: www.else
locomotor
etv i al.,
e r . c1983;
muscle
o m / l o c aLight
t e / a u tet
afferents
n eal.,
causes
u 2008) (Fig. 1) that project
contribution to the development of central fatigue has only been inves- available on the effects of other diseases characterized by abnormal tigue, uncom
activation. Both components of fatigue have previously a reduced muscle
been linked to blood via the flow/O dorsal 2 delivery
horn of the and spinalaccelerated
cord (Wilson rateand ofHand,
periph- 1997; Wilson
tigated in the last 40 years (Bigland-Ritchie et al., 1986). neural feedback from group III/IV muscle afferents (e.g., hypertension) etc.).
group III and IV muscle afferent feedback. eral fatigue (Amann et and al.,Secher,
2002) to 2010,
various 2011a,spinal2011b), and supraspinal it couldsites be spec-
within the Afferen
CNS
With the exception of a few experimental approaches to reduce on the development of central and et peripheral fatigue during
ulated that arterial baroreflex
(Brooks buffering
al., 2005; Craig, of group 1995; Craig,exercise.
III/IV-mediated 2003). Althoughmusclefirst the rolelegof (~9 m
sensory feedback during and after exercise in humans [e.g. (Gandevia
Autonomic
reflexes responses
exacerbates to exercise:
group
the III/IV Groupmuscle
development III/IV
afferentsmuscle in the
of peripheral afferents
circulatory fatigueregulation
during utively
during exerc
exer-
et al., 1990)], the majority of investigations have
☆ Funding for this work‘artificially’ increased
was received from the National Institutes of Health (HL-103786 cise has been
exercise. ☆ However, Waldrop andrecognized
Mitchell nearly have shown 80 years that ago (Alam and Smirk, 1937),
the arterial
 Autonomic Neuroscience: Basic and Clinical xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Autonomic Neuroscience: Basic and Clinical

journal homepage: www.elsevier.com/locate/autneu

Autonomic responses to exercise: Group III/IV muscle afferents

and fatigue☆
Markus Amann a,b,⁎, Simranjit K. Sidhu a, Joshua C. Weavil b, Tyler S. Mangum b, Massimo Venturelli c
a
Department of Medicine, University of Utah, Salt Lake City, UT, USA
b
Department of Exercise & Sport Science, University of Utah, Salt Lake City, UT, USA
c
Department of Biomedical Sciences for Health, University of Milan, Italy

a r t i c l e i n f o a b s t r a c t
Obsevaciones: Aferentes musculares III y IV juegan un rol significativo en el desarrollo de la
fatiga
Article durante el ejercicio. Esas Group
history: neuronas determinan
III and IV muscle respuestas
afferents originating autonómicas
in exercising limb muscle play aal ejercicio
significant role in para
the development
Received 12 June 2014 of fatigue during exercise in humans. Feedback from these sensory neurons to the central nervous system (CNS)
asegurar
Received un
in revised adecuado
form flujo sanguíneo
17 September 2014 y aporte
reflexively increases de oxígeno.
ventilation Sin embargo,
and central (cardiac los mismos
output) and peripheral aferentes
(limb blood flow) hemodynamic
Accepted 13 October 2014
ejercen efectos
Available online xxxx
inhibitorios en el SNC,
responses lo que
during facilita
exercise la
and therebyfatiga
assuresyadequate
deterioramuscleel rendimiento
blood flow and O2 delivery. This response de-
picts a key factor in minimizing the rate of development of peripheral fatigue and in optimizing aerobic exercise
Keywords:
capacity. On the other hand, the central projection of group III/IV muscle afferents impairs performance and limits
Neural feedback the exercising human via its diminishing effect on the output from spinal motoneurons which decreases volun-
Central fatigue tary muscle activation (i.e. facilitates central fatigue). Accumulating evidence from recent animal studies suggests
Exercise pressor reflex the existence of two subtypes of group III/IV muscle afferents. While one subtype only responds to physiological
Circulation and innocuous levels of endogenous intramuscular metabolites (lactate, ATP, protons) associated with ‘normal’,
Ventilation predominantly aerobic exercise, the other subtype only responds to higher and concurrently noxious levels of
AUTNEU-01705; No of Pages 5
metabolites present in muscle during ischemic contractions or following, for example, hypertonic saline infu-
sions. This review discusses the mechanisms through Autonomic Neuroscience:
which group Basic andafferent
III/IV muscle Clinical xxx (2014) xxx–xxx
feedback mediates
both central and peripheral fatigue in exercising humans. We also briefly summarize the accumulating evidence
from recent animal and human studies documenting the existence of two subtypes of group III/IV muscle affer-
Contents lists available at ScienceDirect
ents and the relevance of this discovery to the interpretation of previous work and the design of future studies.
© 2014 Published by Elsevier B.V.
Autonomic Neuroscience: Basic and Clinical
1. Introduction In order to assure a sufficient link to the original work in the face of a
journal homepage: www.elsevier.com/locate/autneu
restricted number of references, we would be citing various other
Existe un umbral para descarga de los metaboloreceptores?
 umbral de descarga para el
metaboloreflejo de un
pH muscular = 6.90

50% MCV con diferentes tiempos

de ejercitación
Umbral Crítico de Fatiga Periférica
 Fatiga Central durante el ejercicio.

Amann (2011) Umbral crítico de fatiga

periférica.

La fatiga ocurre ante una cierta

cantidad de señales metabólicas
las que aumentan las aferencias
musculares III/IV
Conclusión:

Pi es la causa primaria de fatiga periférica.

La acumulación de H+ contribuye a la fatiga central

durante el ejercicio, probablemente actuando sobre
los aferentes musculares III/IV.
 Posible asociación entre aferentes musculares y
la fatiga temprana en personas con enfermedades crónicas

reposo
Actividad
Aferentes Umbral crítico de fatiga
Musculares Periférica
III/IV Con enfermedad
Acumulación
de metabolitos Sin enfermedad

@jcancino
 Posible
Posible asociaciónentre
asociación entre aferentes
aferentesmusculares y y
musculares
la fatiga
la fatiga temprana
temprana enen sujetos con
personas conenfermedades crónicas
enfermedades crónicas

Caminata a moderada intensidad

Actividad
Aferentes Con enfermedad Umbral crítico de fatiga
Musculares Periférica
III/IV
Sin enfermedad
Acumulación
de metabolitos
Respuesta CV elevada
Disnea

@jcancino
 Posible
Posible asociaciónentre
asociación entre aferentes
aferentesmusculares y y
musculares
la fatiga
la fatiga temprana
temprana enen sujetos con
personas conenfermedades crónicas
enfermedades crónicas

Carrera alta intensidad

Actividad
Aferentes Sin enfermedad Con enfermedad Umbral crítico de fatiga
Musculares Periférica
III/IV

Acumulación
de metabolitos

@jcancino
Asociación con el rendimiento
60 MCV de 3’’ c/ 2” pausa
Control vs Fentanilo
31P-MRS

“los ergoreceptores limitan el rendimiento

al inicio del ejercicio”.

+8%
 J Physiol 594.18 (2016) pp 5303–5315 5303

Group III/IV muscle afferents limit the intramuscular

metabolic perturbation during whole body exercise
in humans
Gregory M. Blain1 , Tyler S. Mangum2 , Simranjit K. Sidhu3,6 , Joshua C. Weavil2 , Thomas J. Hureau1,3 ,
Jacob E. Jessop5 , Amber D. Bledsoe5 , Russell S. Richardson2,3,4 and Markus Amann2,3,4,5
1
LAMHESS, EA 6312, University Nice Sophia Antipolis, University of Toulon, Nice, France
2
Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT, USA
3
Department of Medicine, University of Utah, Salt Lake City, UT, USA
4
Geriatric Research, Education, and Clinical Centre, Salt Lake City VAMC, UT, USA
8 sujetos realizaron una carrera de 5 km ciclismo (time trial) bajo
5
6
Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA
Discipline of Physiology, School of Medicine, The University of Adelaide, Australia
condiciones normales (control) o luego de inyección intratecal de
Fentanilo
The Journal of Physiology

! The purpose
Key points
Biopsias musculares fueron obtenidas antes y después del
of this study was to determine the role of group III/IV muscle afferents in limiting
ejercicio. the endurance exercise-induced metabolic perturbation assayed in muscle biopsy samples taken

! Lumbar intrathecal fentanyl was used to attenuate the central projection of µ-opioid
Actividad de motoneuronas fue valorada fromalocomotor
través de EMG de vasto
muscle.
latetal.
! The findings suggest that the central projection of group III/IV muscle afferent feed-
receptor-sensitive locomotor muscle afferents during a 5 km cycling time trial.

back constrains voluntary neural ‘drive’ to working locomotor muscle and limits the

!
exercise-induced intramuscular metabolic perturbation.
Therefore, the CNS might regulate the degree of metabolic perturbation within locomotor
muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents
are an important neural link in this regulatory mechanism, which probably serves to protect
locomotor muscle from the potentially severe functional impairment as a consequence of severe
intramuscular metabolic disturbance.

Abstract To investigate the role of metabo- and mechanosensitive group III/IV muscle afferents
in limiting the intramuscular metabolic perturbation during whole body endurance exercise, eight
subjects performed 5 km cycling time trials under control conditions (CTRL) and with lumbar
 Power output (W) 221 ± 9 220 ± 10 220 ± 9 243 ± 13# 197 ± 14#,∗ 220 ± 12
VL RMS (% MVC) 50 ± 19 61 ± 22 55 ± 20 69 ± 16# 70 ± 14 69 ± 16#
RF RMS (% MVC) 24 ± 8 27 ± 11 25 ± 9 39 ± 19# 35 ± 25 37 ± 22#
Data are expressed as group mean ± SEM. VL RMS, root mean square (RMS) of the vastus lateralis EMG signal normalized to the RMS
recorded during pre-exercise maximal voluntary contraction (MVC); RF RMS, RMS of the rectus femoris EMG signal normalized to the
RMS recorded during pre-exercise MVC.
∗ P < 0.05 vs 0–2.5 km; # P < 0.05 vs control.

degree of end-exercise peripheral fatigue following FENT Accumulating evidence suggests that peripheral fatigue
might, at least in part, be accounted for by the effect of is constrained during strenuous whole body exercise,
the higher levels of either Pi or H+ , or the combination possibly to a critical threshold. Indeed, consistent with
of both (Nelson et al. 2014). These strong relationships previous findings (Amann et al. 2009, 2011a; Gagnon
J Physiol 594.18 (2016) pp 5303–5315
probably reflect5303
the critical role of these metabolites in the et al. 2012; Sidhu et al. 2014), the current results confirm
development of peripheral fatigue (Allen et al. 2008), but that the restriction of peripheral fatigue to a specific
also highlight the apparent modulation of this process by level is mediated by group III/IV muscle afferent feed-
Group III/IV muscle afferents limit the intramuscular group III/IV afferent feedback. back. As illustrated in Fig. 4, greater peripheral fatigue

metabolic perturbation during whole body exercise

in humans 600 Control
* 700 *
–10
0

Fentanyl 600

% change from baseline

% change from baseline

% change from baseline

500 –20
Gregory M. Blain1 , Tyler S. Mangum2 , Simranjit K. Sidhu3,6 , Joshua C. Weavil2 , Thomas J. Hureau1,3 , 500
–30
Jacob E. Jessop5 , Amber D. Bledsoe5 , Russell S. Richardson2,3,4 and Markus Amann2,3,4,5 400
400 –40
1
LAMHESS, EA 6312, University Nice Sophia Antipolis, University of Toulon, Nice, France 300 –50
2 300
Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT, USA
3
Department of Medicine, University of Utah, Salt Lake City, UT, USA 200 –60
200

La acumulación de
4
Geriatric Research, Education, and Clinical Centre, Salt Lake City VAMC, UT, USA –70
5
Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA 100 100
6
–80
Discipline of Physiology, School of Medicine, The University of Adelaide, Australia
*

metabolitos fue mayor al

0 0 –90
Inorganic phosphate Adenosine diphosphate Phosphocreatine
The Journal of Physiology

1400 7.0

!
Key points *

momento de la fatiga en la
The purpose of this study was to determine the role of group III/IV muscle afferents in limiting 1200
6.9

% change from baseline

the endurance exercise-induced metabolic perturbation assayed in muscle biopsy samples taken 1000

condición
! de Fentanilo
from locomotor muscle. #

Muscle pH
6.8
800
Lumbar intrathecal fentanyl was used to attenuate the central projection of µ-opioid

!
receptor-sensitive locomotor muscle afferents during a 5 km cycling time trial. 600 6.7
The findings suggest that the central projection of group III/IV muscle afferent feed- *
400
back constrains voluntary neural ‘drive’ to working locomotor muscle and limits the

!
6.6
exercise-induced intramuscular metabolic perturbation. 200
Therefore, the CNS might regulate the degree of metabolic perturbation within locomotor
0 6.5
muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents Lactate Baseline Post-exercise
are an important neural link in this regulatory mechanism, which probably serves to protect
locomotor muscle from the potentially severe functional impairment as a consequence of severe Figure 2. Effect of attenuating group III/IV afferent feedback on intramuscular metabolic perturbations
intramuscular metabolic disturbance. evoked by a 5 km cycling time trial
Muscle samples were obtained from the vastus lateralis immediately after exercise. An occlusion cuff placed at
the top of the thigh was inflated at the end of exercise and maintained at 250 mmHg until muscle sampling was
completed (<30 s). Muscle pH and metabolite data are expressed in absolute units and per cent change from
Abstract To investigate the role of metabo- and mechanosensitive group III/IV muscle afferents baseline, respectively. ∗ P < 0.05 vs control; # P < 0.001 vs baseline.
in limiting the intramuscular metabolic perturbation during whole body endurance exercise, eight
subjects performed 5 km cycling time trials under control conditions (CTRL) and with lumbar C 2016 The Authors. The Journal of Physiology ⃝
⃝ C 2016 The Physiological Society

intrathecal fentanyl impairing lower limb muscle afferent feedback (FENT). Vastus lateralis muscle
biopsies were obtained before and immediately after exercise. Motoneuronal output was estimated
through vastus lateralis surface electromyography (EMG). Exercise-induced changes in intra-
muscular metabolites were determined using liquid and gas chromatography-mass spectrometry.
Quadriceps fatigue was quantified by pre- to post-exercise changes in potentiated quadriceps
twitch torque (!QTsingle ) evoked by electrical femoral nerve stimulation. Although motoneuronal
output was 21 ± 12% higher during FENT compared to CTRL (P < 0.05), time to complete
the time trial was similar (!8.8 min). Compared to CTRL, power output during FENT was
10 ± 4% higher in the first half of the time trial, but 11 ± 5% lower in the second half (both
P < 0.01). The exercise-induced increase in intramuscular inorganic phosphate, H+ , adenosine
J Physiol594.18 Muscle afferents limit metabolic perturbation 5309

Intrathecal fentanyl was used to attenuate the central therefore voluntary muscle activation, group III/IV muscle
projection of µ-opioid receptor-sensitive locomotor afferent feedback limits the intramuscular metabolic
muscle afferents during a 5 km cycling time trial and J Physiol 594.18
perturbation during(2016) pp 5303–5315
whole body endurance exercise. 5303
the impact on the intramuscular milieu examined. This Furthermore, the current data suggest that the group
approach revealed that, probably through the inhibitory III/IV-mediated restriction of motoneuronal output to
influence on motoneuronal output (i.e. neural drive) and
Group III/IV muscle afferents limit the intramuscular
the locomotor muscle determines the amount of tolerable
exercise-induced peripheral fatigue during intense cycling
metabolic perturbation during whole body exercise
exercise. This inference is supported by a significant
relationship between the change in several indices of
330
* Control (8.8 ± 0.4 min)
Fentanyl (8.8 ± 0.5 min) in humans
the intramuscular environment and the change in peri-
pheral fatigue in FENT compared to CTRL. Therefore,
310 W peak
it appears that group III/IV muscle afferents are an
Power output (W)

1 2
290
importantGregory
neuralM. Blain
link in a,regulatory
Tyler S. Mangum
mechanism , Simranjit
designed K. Sidhu3,6 , Joshua C. Weavil2 , Thomas J. Hureau1,3 ,
270 Jacob
to protect E. Jessop5 ,muscle
locomotor Amber D. Bledsoe
from 5
Richardson2,3,4 and Markus Amann2,3,4,5
, Russell S.intra-
an abnormal
250 muscular metabolic disturbance by limiting peripheral
* 1
230 fatigue. 2 LAMHESS, EA 6312, University Nice Sophia Antipolis, University of Toulon, Nice, France
Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT, USA
210 3
Department of Medicine, University of Utah, Salt Lake City, UT, USA
190 Site of action
Geriatric of
4
intrathecal
Research, fentanyl
Education, and Clinical Centre, Salt Lake City VAMC, UT, USA
170
∼4 min
5
A migration
6 of Aunque la actividad EMG fue mayor en la condición
Department of Anesthesiology, University of Utah, Salt Lake City, UT, USA
fentanyl within the cerebrospinal
Discipline of Physiology, School of Medicine, fluid Australia
The University of Adelaide,
de Fentanilo, la potencia promedio fue la misma en
90 to the opioid-sensitive areas of the brain involved in the
VL EMG (% of baseline MVC)

* cardioventilatory response to exercise (Caringi et al. 1998;

80
The Journal of Physiology ambas condiciones.
Lalley, 2008) would negate the implications of the current

ventilatory and the! HR

Key points
70 findings. Therefore, to address this concern, both the
The response
purpose ofto
thisarm cranking
study exercisethe role of group III/IV muscle afferents in limiting
was to determine
60 was assessed in FENT theand CTRLexercise-induced
endurance conditions. The similar
metabolic perturbation assayed in muscle biopsy samples taken

with and without !lumbar

50 cardioventilatory responses to arm
from locomotor cranking performed
muscle.
Lumbar intrathecal fentanylwas
intrathecal fentanyl exclude
used ato attenuate the central projection of µ-opioid

! The findings
40
En conclusión, durante el ejercicio, los aferentes
significant drug migration beyond locomotor
receptor-sensitive
the binding of fentanyl
the cervical
directly suggest
to the that
opioid
levelafferents
muscle and during a 5 km cycling time trial.
30 the receptors
central projection of group III/IV muscle afferent feed-
musculares del grupo III / IV proporcionan
in the brain (Amann et al. 2010). However, we do not
back constrains voluntary neural ‘drive’ to working locomotor muscle and limits the
fentanyl attenuates! muscle afferent feedback by inhibiting
60 know whether the stimulation of µ-opioid receptors with
* * exercise-induced intramuscular metabolic perturbation.
retroalimentación al SNC que, a su vez, restringe la
RF EMG (% of baseline MVC)

50 postsynaptic actionsTherefore, the CNS

or presynaptic mightofregulate
release the degree
substance P, of metabolic perturbation within locomotor
muscle and thereby limit peripheral fatigue. It appears that the group III/IV muscle afferents
40
or both.
salida motoneuronal al músculo esquelético activo.
are an important neural link in this regulatory mechanism, which probably serves to protect

30 Este mecanismo regulador limita la perturbación

locomotor muscle from the potentially severe functional impairment as a consequence of severe
Muscle afferents, intramuscular metabolic
intramuscular metabolic disturbance.
perturbation and muscle contractile function
20 metabólica intramuscular inducida por el ejercicio,
Fentanyl blockade greatly increased the exercise-induced
10
0 1 2 3 4 5
previniendo
intramuscular metabolic
Abstract To
whole body endurance
perturbation
exercise.
in limiting
unthedesafío
investigate during
Specifically,
the intramuscular
homeostático
intense
role of metabo-
the greater
metabolic
anormal
and mechanosensitive group III/IV muscleyafferents
fatiga
perturbation during whole body endurance exercise, eight
as evidenced byperiférica in excesiva.
Distance (km) breakdown of PCr and the
subjects increased
performed 5 kmrate of time
cycling glycolysis,
trials under control conditions (CTRL) and with lumbar
the increase
intrathecal intramuscular
fentanyl impairing lowerlactate, in afferent feedback (FENT). Vastus lateralis muscle
limb muscle
Figure 1. Effect of attenuating group III/IV afferent feedback FENT compared to CTRL resulted in higher levels of
on power output and quadriceps EMG during 5 km cycling biopsies were obtained before and immediately after exercise. Motoneuronal output was estimated
intramuscular Pi and ADP and a more severe acidosis
time trial through vastus lateralis surface electromyography (EMG). Exercise-induced changes in intra-
(Fig. 2). Concomitant with this greater accumulation of
Each data point represents the average over the preceding 100 m
section. Vastus lateralis (VL) and rectus femoris (RF) RMS EMGs were metabolites, somemuscular
known to metabolites
determine were determinedfatigue
peripheral using liquid and gas chromatography-mass spectrometry.
normalized to the RMS recorded during pre-exercise MVC. Subjects
Quadriceps
(Allen et al. 2008), fatigue was quantified
the exercise-induced by pre- in
reduction to post-exercise changes in potentiated quadriceps
were required to reach an individual target power output twitch
twitch torque across torquestimulation
various (!QTsingle ) evoked by electrical
frequencies wasfemoral nerve stimulation. Although motoneuronal
(260 ± 15 W) before the race was launched. Although the overall VL output
significantly greater was 21compared
in FENT ± 12% higher during(Fig.
to CTRL FENT 3).compared to CTRL (P < 0.05), time to complete
and RF EMGs were significantly higher during FENT (◦) compared to the time trial wasassimilar
Furthermore, when expressed per (!8.8
cent min). Compared to CTRL, power output during FENT was
difference
CTRL (•), the average power output was similar between the two
trials. Wpeak : peak power output measured during the maximal between FENT and 10 CTRL,
± 4% higher
changesin the
infirst half of thetwitch
quadriceps time trial, but 11 ± 5% lower in the second half (both
incremental exercise test (296 ± 37 W). Data are presented as group P < 0.01). The
torques and intramuscular Pi exercise-induced
and pH were increase in intramuscular inorganic phosphate, H+ , adenosine
correlated
mean ± SEM. ∗ P < 0.05 vs control. (Fig. 4). These correlations
diphosphate, suggest
lactate andthat the additional
phosphocreatine depletion was 55 ± 30, 62 ± 18, 129 ± 63, 47 ± 14
(P < 0.001) and 27 ± 14% (P < 0.01) greater in FENT than CTRL. !QTsingle was greater
C 2016 The Authors. The Journal of Physiology ⃝
⃝ C 2016 The Physiological Society following FENT than CTRL (−52 ± 2 vs −31 ± 1%, P < 0.001) and this difference was positively
Qué ocurre cuando el ergoreflejo se provoca en la musculatura ventilatoria?
 Reflejo metabólico (Dempsey, 1997, 2006)

El aumento del trabajo respiratorio

Estimula aferentes III/IV las que
potencian
La estimulación simpática
incrementando
La vasoconstricción en las
extremidades
Ejercitadas y con ello disminuyendo el
Rendimiento y aumentando la
percepción
De la fatiga.
 El ergoreflejo en la génesis de la tolerancia al
ejercicio y la fatiga
Menor capacidad
Mayor descarga
para hacer frente a
para hacer frente a
la demanda de la
la demanda de la
actividad (-) (+) actividad
Ergoreflejo
Atenuación de la (-) Exacerbación de la
respuesta respuesta
cardiorespiratoria cardiorespiratoria

Desarrollo de la Desarrollo de la
fatiga con un mayor Mayor tolerancia a
fatiga con un mayor
componente la fatiga frente a una
componente central
periférico misma carga
 Flujo del aumento en la tolerancia al
ejercicio
Igual
costo Adaptación al Menor dependencia anaeróbica
para la ejercicio para la producción de energía
actividad

Menor descarga aferente de

ergoreceptores

Mayor
duración Mayor tolerancia Menor demanda ventilatoria y
y/o menor al ejercicio circulatoria
percepción de
esfuerzo
 Review
Eu
Angius and Crisafulli 7 C

Exercise intolerance and fatigue 0(

!
C

Chronic heart failure

in chronic heart failure: is there a A
sa
role for group III/IV afferent feedback? D
jo

Reduced cardiac output and skeletal Luca Angius1 and Antonio Crisafulli2
muscle perfusion during exercise

Pharmacological intervention?
Abstract
Myopathy, reduction in muscle mass,
alterations in muscle metabolism Exercise intolerance and early fatiguability are hallmark symptoms of chronic heart failure. W
Aunque se demostró en algunos estudios, la
the heart is certainly the leading cause of chronic heart failure, the patho-physiological mecha
ance in these patients are more complex, multifactorial and only partially understood. Some e
fatiga muscular inducida por el ejercicio en la
potential role of an exaggerated afferent feedback from group III/IV muscle afferents in the ge
Overactivity of feedback from these muscle afferents may cause exercise intolerance with a d
población clínica se puede atribuir
cardiovascular dysregulation, by reducing motor output and by facilitating the development
Increased group III/IV Increased perceived exertion,
muscle afferents activity reduced motor output parcialmente a una actividad más alta y / o
fatigue during exercise. Importantly, physical inactivity appears to affect the progression of the s
physical training can partially counteract this condition. In the present review, the role playe
anormal de los aferentes musculares del
feedback in cardiovascular regulation during exercise and exercise-induced muscle fatigue of
potential role in inducing exercise intolerance in chronic heart failure patients will be summa
grupo III / IV y también puede explicar la
Exaggerated exercise pressor
reflex activation
capacidad
Keywords reducida de ejercicio y la
Metabo-reflex, fatiguability, circulation, exercise pressor reflex, sensory neurons, muscle fatigu
intolerancia al ejercicio de los pacientes con
Received 22 October 2019; accepted 27 January 2020
CHF.
Early fatigue and and, in recent years, there has b
Hemodynamic alterations, reduced exercise Introduction that these changes play a pivo
exaggerated vasconstriction
during effort tolerance Exercise intolerance and early fatiguability are hall- ment of exercise intolerance a
mark symptoms of chronic heart failure (CHF). exercise capacity. Some clues p
These symptoms severely limit daily activities and ence of a peripheral reflex th
have been traditionally considered as the consequence secondary to the described ske
Sedentary lifestyle, of the inability of the heart to meet the metabolic and may contribute to the exer
Physical training
muscle disuse and atrophy
demand of the muscles during exercise, with the mal- early fatiguability experienced
function of the heart as a pump as the leading cause.1 particular, it has been reporte
However, the pathophysiological mechanisms of exer- systems (i.e. renin–angiotensin
Figure 1. Putative mechanisms responsible for the exercise intolerance and early fatigue induced by type III/IV afferent cisefeedback in
intolerance in CHF are more complex, multifactor- sin and atrial natriuretic pep
chronic heart failure. Abnormal central haemodynamics initiate a cascade which ultimately results in an increase in III/IV ial afferent
and only partially investigated and understood. and that patients show alter
feedback activity. It is to be emphasised that physical training may potentially counteract this malfunctioning at various levels, while, to
At the heart level, the combination of systolic and system activity at rest and
date, no pharmacological intervention has been demonstrated to be able to correct this abnormal regulation. European Journal of Preventive
diastolic abnormalities concurs in reducing the capacity
Cardiology, 2020
to increase cardiac output (CO). Moreover, several 1
Faculty of Health and Life Sciences, Spo
have been confirmed and support the concept that whether exercise training is effective in reducing the
other abnormalities such as impairments in peripheral Northumbria University, UK
exaggerated EPR activity is at least in part responsible exaggerated EPR in these patients. endothelial-dependent vasodilation, reduction in sys- 2
Department of Medical Sciences and Pu
for the sympathetic overactivity in CHF patients, and temic oxygen delivery, reduction in pulmonary reserve Laboratory, University of Cagliari, Italy
that this condition can be successfully counteracted by and respiratory muscle perfusion have all been
Mecanismos de fatiga

Dr. Jorge Cancino L. PhD.

Avda. Pedro de Valdivia 1509
Providencia, Santiago
+56 2 2420 7100
www.finisterrae.cl