This article was downloaded by: [University of Sunderland]

On: 07 January 2015, At: 16:39

Publisher: Routledge
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK

Journal of Sports Sciences

Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/rjsp20

Central and peripheral factors in fatigue

a
J. Mark Davis
a
Department of Exercise Science , University of South Carolina , Columbia, SC, 29208, USA
Published online: 01 Feb 2008.

To cite this article: J. Mark Davis (1995) Central and peripheral factors in fatigue, Journal of Sports Sciences, 13:S1, S49-S53,
DOI: 10.1080/02640419508732277

To link to this article: http://dx.doi.org/10.1080/02640419508732277

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.

This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions
 Journal of Sports Sciences, 1995, 13, S49-S53

Central and peripheral factors in fatigue

J. MARK DAVIS
Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA

The causes of fatigue during muscular exercise include factors that reside in the brain (central mechanisms) as
well as the muscles themselves (peripheral mechanisms). Central fatigue is largely unexplored, but there is
increasing evidence that increased brain serotonin (5-HT) can lead to central (mental) fatigue, thereby causing
a deterioration in sport and exercise performance.
Although there are also strong theoretical grounds for a beneficial role of nutrition in delaying central fatigue,
the data are much more tenuous. Dietary supplementation with branched-chain amino acids (BCAA) in low
doses produces small and probably inconsequential effects on peripheral markers of brain 5-HT synthesis
Downloaded by [University of Sunderland] at 16:39 07 January 2015

(plasma free tryptophan/BCAA), whereas larger doses are likely to be unpalatable, reduce the absorption of
water in the gut, and may increase potentially toxic ammonia concentrations in the plasma. Alternatively,
carbohydrate supplementation results in large reductions in plasma free tryptophan/BCAA and exercise time to
fatigue is significantly longer, but it is difficult to distinguish between the effects of carbohydrate feedings on
central fatigue mechanisms and the well-established beneficial effects of carbohydrate supplements on the
contracting muscle. These data support the exciting possibility that relationships exist among nutrition, brain
neurochemistry and sport performance. However, while the evidence is intriguing and makes good intuitive
sense, our knowledge in this area is rudimentary at best.

Keywords: Brain, dopamine, endurance, exercise, serotonin, tryptophan.

Introduction Unfortunately, a role for central fatigue during exer-

cise is often accepted only by default when the inves-
The causes of fatigue during muscular exercise are tigator is unable to find support for the hypothesis of a
numerous and can result from an impairment any- muscle dysfunction. This is true even though it has
where along the chain of command from motor centres been known for over a century that 'psychological
in the brain to the actin-myosin crossbridges in the factors' can affect exercise performance (Asmussen,
muscle fibre (Enoka and Stuart, 1992; Green, 1987). 1979; Sécher, 1992) and that under most circumstan-
Fatigue associated with factors that reside within the ces fatigue results from the individual's unwillingness
central nervous system are referred to as central mech- to generate adequate central drive to maintain the force
anisms, whereas those that affect the muscle directly or power output. This is also exemplified by the fact
are peripheral mechanisms. that the often debilitating fatigue that accompanies
Peripheral mechanisms of fatigue have been well infection, chronic fatigue syndrome, and depression are
studied and include specific impairments in neuromus- almost certainly not due to impairments within the
cular transmission and impulse propagation, dysfunc- muscle.
tion within the sarcoplasmic reticulum involving The lack of reasonable hypotheses to explain central
calcium release and uptake, substrate depletion, and fatigue has severely limited research in this area. Evi-
various other metabolic factors that disrupt energy pro- dence is accumulating in support of a role of the neuro-
vision and contraction. The details of these impair- transmitters serotonin (5-HT or 5-hydroxytryptamine)
ments can be found in excellent reviews published and dopamine in central fatigue during prolonged exer-
elsewhere (Coggan and Coyle, 1991; Enoka and cise. First, I will review the basic tenets of this hypo-
Stuart, 1992; Fitts and Metzger, 1993; Green, 1987). thesis and the scientific evidence regarding its validity;
This review will focus on the much less well studied then I will address the more limited evidence regarding
aspect of central fatigue. a possible role of nutrition in delaying central fatigue.
0264-0414/95 © 1995 E. & F.N. Spon
 S50 Davis

Brain 5-HT and central fatigue include a study of the relationship between exercise
fatigue and changes in brain 5-HT and dopamine (DA;
Newsholme et al. (1987) were the first to propose a role a neurotransmitter involved in motivation, arousal and
for 5-HT as a mediator of central fatigue during exer- neuromuscular control) in rats. Measurements of
cise. They focused on brain 5-HT because of its well- 5-HT and DA, and their primary metabolites 5-HIAA
known effects on arousal, lethargy, sleepiness and and DOPAC, were made in the midbrain, striatum,
mood (Young, 1986), and the realization that exercise hypothalamus and hippocampus of rats sacrificed at
could affect important factors controlling brain 5-HT rest, following 1 h of treadmill exercise at a pace set to
synthesis and turnover. elicit approximately 60-65% VO2 max, and at fatigue
This hypothesis suggests that increased brain 5-HT (3 h). The concentrations of 5-HT and 5-HIAA were
can lead to central fatigue during prolonged exercise, higher in all brain regions at 1 h except for the hippo-
thereby causing a deterioration in sport and exercise campus where only 5-HIAA was elevated. At fatigue,
performance (Newsholme et al, 1987). Increased brain 5-HT remained elevated, whereas 5-HIAA increased
5-HT synthesis occurs in response to an increase in the even further in the midbrain and striatum. Dopamine
delivery to the brain of blood-borne tryptophan (TRP), and DOPAC increased in most brain regions after 1 h
an amino acid precursor to 5-HT. Most of the TRP in of exercise, but then decreased at fatigue. These data
Downloaded by [University of Sunderland] at 16:39 07 January 2015

blood plasma circulates loosely bound to albumin, but show a good association between increased brain 5-HT
it is the unbound or free tryptophan (f-TRP) that is and fatigue during prolonged exercise. Interestingly,
transported across the blood-brain barrier. This trans- brain DA, which has been linked with increased
port occurs via a specific mechanism that TRP shares arousal, motivation, muscular coordination and
with other large neutral amino acids, most notably the increased endurance performance (Heyes et al, 1985),
branched-chain amino acids (BCAAs) leucine, iso- actually decreased towards the end of prolonged exer-
leucine and valine. Thus, brain 5-HT synthesis will cise as fatigue developed. The significance of the appar-
increase when there is an increase in the ratio of the ent inverse relationship between brain 5-HT and DA as
concentration of free tryptophan (f-TRP) in blood fatigue develops is interesting but requires further
plasma to the total plasma concentration of BCAAs investigation.
(i.e. when f-TRP/BCAA rises). They proposed that this Bailey et al. (1992, 1993a, 1993b) also completed a
would occur during prolonged exercise, as (1) BCAA series of experiments to better approach the question of
are taken up from the blood and oxidized for energy in cause and effect by testing the effects of specific drug-
contracting skeletal muscles and (2) plasma free fatty induced alterations in brain 5-HT activity on fatigue in
acids (FFAs) increase, which causes a parallel increase rats. The administration of drugs that specifically
in plasma f-TRP because FFAs displace TRP from its increased the activity of brain 5-HT reduced treadmill
usual binding sites on albumin. run time to exhaustion in a dose response manner in
rats, whereas a drug that decreased brain 5-HT activity
delayed fatigue (Fig. 1). The supposition that these
Evidence for a role for brain 5-HT in drug-induced effects resulted from specific alterations
central fatigue in brain 5-HT activity is supported by the observation
that fatigue could not be explained by alterations in
Early animal studies by Chaouloff et al. (1986a, 1986b, body temperature, blood glucose, muscle and liver gly-
1987, 1989) and Blomstrand et al. (1989) showed that cogen, or various stress hormones (Bailey et al,
1—2 h of treadmill running caused marked increases in 1993b). These findings involving the effects of drug-
plasma f-TRP (but not total TRP), as well as brain con- induced increases in brain 5-HT activity were recently
centrations of TRP, 5-HT and 5-HIAA (the primary confirmed in human subjects who were given either
metabolite of 5-HT). Similar increases in TRP and paroxetine or fluoxetine (5-HT re-uptake blockers that
5-HIAA were also found in cerebrospinal fluid follow- act as 5-HT agonists) (Davis et al, 1993; Wilson and
ing exercise that returned to basal levels within 1 h. Maughan, 1992). When these drugs were administered
These data were important in establishing that increa- prior to prolonged running or cycling to fatigue at 70%
ses in plasma f-TRP and f-TRP/BCAA were primary VO2 max, exercise time was reduced (Wilson and
factors leading to the increase in brain 5-HT synthesis Maughan, 1992) and perceived exertion was higher
and turnover during prolonged exercise. However, the (Davis et al, 1993) compared with the placebo trial.
specific relevance of these findings to fatigue per se was There were no reports of strange side-effects and no
not addressed in these studies. differences were found among various markers of cardi-
Bailey et al. (1993b) extended those observations to ovascular, thermoregulatory and metabolic function.
 Central and peripheral factors in fatigue S51

Nutritional effects on 5-HT and central ratio and thereby decrease the availability of f-TRP to
fatigue the brain for 5-HT synthesis.
Blomstrand, Newsholme and colleagues have
The theoretical possibility that central fatigue could be focused on the administration of BCAA as a way to
delayed by nutritional strategies designed to alter the delay central fatigue. They reported that administration
plasma f-TRP/BCAA ratio is centred around two pri- of 7.5-21.0 g of BCAA before and during a marathon
mary strategies involving BCAA and/or carbohydrate race, a cross-country ski race or a soccer match was
supplementation during exercise. Both of these strate- associated with small improvements, in some subjects,
gies would theoretically decrease the f-TRP/BCAA in both physical (Blomstrand et al, 1988, 1991b) and
mental (Blomstrand et al, 1991a) performance. How-
ever, it should be noted that while field studies such as
¿UU
H I males these are designed to mimic the real-world situation
| | females that athletes find themselves in, they are often limited
in scientific value. For example, it is difficult to match
the groups of subjects or to 'blind' them to the experi-
'S 150
mental treatments. It is also very difficult to control
E
c
• important variables like exercise intensity and food and
Downloaded by [University of Sunderland] at 16:39 07 January 2015

o
V)

I 100
• _
water intake. Scepticism about these results is also
heightened by the observations in recent well-control-
led laboratory experiments that BCAA supplementa-
•
X •

o i—=-| tion was not associated with improved performance

(Galiano et al, 1991; Lehmann et al, 1994; Varnier et
4-1

a> T i
E al, 1994; Verger et al, 1994).

1JDLm
c 50 . HHJ
It is also important to note that the administration of
large amounts of BCAAs that would be necessary to
produce physiologically significant alterations in
n plasma f-TRP/BCAA would probably increase plasma
1 2.5 ammonia, which can be toxic to the brain and may also
ÖD (mg kg-1) negatively affect muscle metabolism (Banister and
Cameron, 1990; Calders et al, 1994; Wagenmakers et
al, 1991). It is also possible that this would slow water
absorption across the gut and cause gastrointestinal
disturbances.
A more appropriate strategy for delaying central
fatigue involves carbohydrate feedings, because very
large attenuations in f-TRP and f-TRP/BCAA would
probably be achieved during exercise without the
potential negative conséquences of administering large
doses of BCAA. This is because of the well-established
suppressive effects of carbohydrate feedings on the
mobilization of free fatty acids which compete with f-
TRP for binding sites on plasma albumin molecules
(Davis et al, 1992). These effects might occur in addi-
tion to the well-known benefits of carbohydrate supple-
ments on the peripheral mechanisms of fatigue
(Coggan and Coyle, 1991).
This hypothesis was tested in a double-blind,
0.0 0.5 1.0 1.5 placebo-controlled study in our laboratory in which
LY (mg kg"1) subjects drank 5 ml kg"1 h"1 of either water, a 6% car-
Figure 1 Effects of administering different doses of (a) a bohydrate-electrolyte drink or a 12% carbohydrate-
5-HT agonist (quipazine dimaleate; QD) and (b) a 5-HT electrolyte drink during prolonged cycling at 70% VO2
antagonist (LY 53,857) on run time to fatigue in rats. max to fatigue (Davis et al, 1992). When the subjects
*P < 0.05 versus vehicle (0 dose); # P < 0.05 versus the 1 consumed the water, plasma f-TRP increased by seven-
mg kg~ ' dose. Reprinted with permission from Bailey et al. fold (in direct proportion to plasma free fatty acids),
(1993a). while plasma total-TRP and BCAA changed very little
 S52 Davis

during the ride. When the subjects consumed either the Overall summary and conclusions
6% or 12% carbohydrate-electrolyte solution, the
increases in plasma f-TRP were greatly reduced and Fatigue during prolonged muscular exercise has tradi-
fatigue was delayed by approximately 1 h (Fig. 2). The tionally been associated with mechanisms that reside in
carbohydrate feedings caused a slight reduction in the muscles themselves. Good evidence is now emerg-
plasma BCAA (19 and 31% in the 6 and 12% CHO ing to support a role of brain 5-HT in central fatigue
trials, respectively), but this decrease was probably during prolonged exercise. Studies have shown that (1)
inconsequential with respect to the very large attenua- the concentrations of 5-HT and its major metabolite
tion (five- to seven-fold) of plasma f-TRP. Although it 5-HIAA increase in several brain regions during pro-
was not possible to distinguish between the beneficial longed exercise and reach a peak at fatigue, (2) the
effects of carbohydrate feedings on central versus increase in brain 5-HT synthesis and turnover almost
peripheral mechanisms of fatigue in this study, it was certainly results from an increase in plasma f-TRP and
interesting that the substantial delay in fatigue could f-TRP/BCAA, and (3) the administration of 5-HT
not be explained by typical markers of peripheral mus- agonist and antagonist drugs can decrease and increase
cle fatigue involving cardiovascular, thermoregulatory run times to fatigue in the absence of any apparent
and metabolic function. peripheral markers of muscle fatigue.
Downloaded by [University of Sunderland] at 16:39 07 January 2015

The scientific evidence is more tenuous regarding a

benefit of proper nutrition on central fatigue. Studies
involving BCAA supplementation are limited, the evi-
dence regarding a performance benefit is mixed, and
there are good reasons to believe that this approach
may not be a viable one. Carbohydrate supplementa-
tion, on the other hand, is associated with large de-
18 creases in f-TRP and f-TRP/BCAA, and fatigue is
16- clearly delayed by this strategy. In this case, however,
¡ 14 A,B
is it not possible to distinguish with certainty the effects
12 ••
of CHO feedings on central fatigue mechanisms and
10-- the well-established beneficial effects of CHO supple-
¡Î 8- mentation on the contracting muscle.
i 6 -
Ul
4-
2
References
Asmussen, E. (1979). Muscle fatigue. Medicine and Science in
.06 Sports and Exercise, 11, 313-321.
• • PLACEBO Bailey, S.P., Davis, J.M. and Ahlborn, E.N. (1992). Effect of
.05 increased brain serotonergic (5-HT 1 C ) activity on
A A 6% CHO A,B
.04 O O 12% CHO
endurance performance in the rat. Acta Physiologica
Scandinavica, 145, 75-76.
.03
Bailey, S.P., Davis, J.M. and Ahlborn, E.N. (1993a). Brain
. 0 2 •• serotonergic activity affects endurance performance in the
rat. International Journal of Sports Medicine, 6, 330-333.
. 0 1 ••
Bailey, S.P., Davis, J.M. and Ahlborn, E.N. (1993b).
Neuroendocrine and substrate responses to altered brain
H 1—I—I 1 1 1 1 1 1 1 1 1-
5-HT activity during prolonged exercise to fatigue.
H 1 1 H
PRE 30 60 90 120 150 180 210 240 Journal of Applied Physiology, 74, 3006-3012.
TIME Banister, E.W. and Cameron, B.J.C. (1990). Exercise-
(min) induced hyperammonemia: Peripheral and central effects.
International Journal of Sports Medicine, II, S129-S142
Figure 2 Plasma f-TRP/BCAA (a) and the correlation (suppl. 2).
between plasma FFA and f-TRP (b) during cycle exercise to Blomstrand, E., Celsing, F. and Newsholme, E.A. (1988).
fatigue in men consuming either a water placebo, a 6% or a Changes in plasma concentrations of aromatic and
12% carbohydrate drink. Note that while all subjects receiv- branched-chain amino acids during sustained exercise in
ing placebo reached fatigue prior to the 255-min time limit, man and their possible role in fatigue. Acta Physiologica
half of the subjects in the carbohydrate groups did not and Scandinavica, 133, 115-121.
were stopped prior to fatigue. Reprinted with permission Blomstrand, E., Perrett, D., Parry-Billings, M. and
from Davis et al. (1992). Newsholme, E.A. (1989). Effect of sustained exercise on
 Central and peripheral factors in fatigue S53

plasma amino acid concentrations and on Fitts, R.H. and Metzger, J.M. (1993). Mechanisms of
5-hydroxytryptamine metabolism in six different brain muscular fatigue. In Principles of Exercise Biochemistry
regions in the rat. Acta Physiologica Scandinavica, 136, (edited by J.F. Poortmans), 2nd edn, Vol. 38, pp. 248-268.
473-481. Basel: Karger.
Blomstrand, E., Hassmen, P. and Newsholme, E.A. (1991a). Galiano, F.J., Davis, J.M., Bailey, S.P., Woods, J.A. and
Effect of branched-chain amino acid supplementation on Hamilton, M. (1991). Physiologic, endocrine and
mental performance. Acta Physiologica Scandinavica, 136, performance effects of adding branch chain amino acids to
473-481. a 6% carbohydrate-electrolyte beverage during prolonged
Blomstrand, E., Hassmen, P., Ekblom, B. and Newsholme, cycling. Medicine and Science in Sports and Exercise, 23,
E.A. (1991b). Administration of branched-chain amino S14.
acids during sustained exercise: Effects on performance Green, H.J. (1987). Neuromuscular aspects of fatigue.
and on plasma concentration of some amino acids. Canadian Journal of Sports Sciences, 12, 7s-19s (suppl.
European Journal of Applied Physiology, 63, 83-88. 1).
Calders, P., Matthys, D. and Pannier, J.L. (1994). BCAA Heyes, M.P., Garnett, E.S. and Coates, G. (1985). Central
administration increases plasma levels of ammonia at dopaminergic activity influences rats' ability to exercise.
exercise in 24 h fasted rats. European Journal of Applied Life Sciences, 36, 671-677.
Physiology, 69, 117 (suppl.). Lehmann, M., Schiestl, G., Schmidt, K., Bauer, S. and
Chaouloff, F., Laude, D., Guezennec, Y. and Elghozi, J.L. Wieland, H. (1994). BCAA supplementation-related
Downloaded by [University of Sunderland] at 16:39 07 January 2015

(1986a). Motor activity increases tryptophan, 5- performance in cyclists. European Journal of Applied
hydroxyindoleacetic acid, and homovanillic acid in
Physiology, 69, 116 (suppl.).
ventricular cerebrospinal fluid of the conscious rat. Journal
Newsholme, E.A., Ackworth, I.N. and Blomstrand, E.
of Neurochemistry, 46, 1313-1316.
(1987). Amino acids, brain neurotransmitters and a
Chaouloff, F., Kennett, G.A., Serrurier, B., Merina, D. and
functional link between muscle and brain that is important
Curson, G. (1986b). Amino acid analysis demonstrates
in sustained exercise. In Advances in Myochemistry (edited
that increased plasma free tryptophan causes the increase
by G. Benzi), pp. 127-133. London: John Libbey/
of brain tryptophan during exercise in the rat. Journal of
Neurochemistry, 46, 1647-1650. Eurotext.
Secher, N.H. (1992). Central nervous influence on fatigue.
Chaouloff, F., Laude, D., Merino, D., Serrurier, B.,
Guezennec, Y. and Elghozi, J.L. (1987). Amphetamine In Endurance in Sport (edited by R.J. Shephard and P.-O.
and alpha-methyl-p-tyrosine affect the exercise induced Åstrand), pp. 96-106. Boston, MA: Blackwell Scientific.
imbalance between the availability of tryptophan and Varnier, M., Sarto, P., Martines, D., Lora, L., Carmignoto,
synthesis of serotonin in the brain of the rat. F., Leese, G. and Naccarato, R. (1994). Effect of infusing
Neuropharmacology, 26, 1099-1106. branched-chain amino acid during incremental exercise
Chaouloff, F., Laude, D. and Elghozi, J.L. (1989). Physical with reduced muscle glycogen content. European Journal
exercise: Evidence for differential consequences of of Applied Physiology, 69, 26-31.
tryptophan on 5-HT synthesis and metabolism in central Verger, P.H., Aymard, P., Cynobert, L., Anton, G. and Luigi,
serotonergic cell bodies and terminals. Journal of Neural R. (1994). Effects of administration of branched-chain
Transmission, 78, 121-130. amino acids vs glucose during acute exercise in the rat.
Coggan, A.R. and Coyle, E.F. (1991). Carbohydrate Physiology and Behaviour, 55, 523-526.
ingestion during prolonged exercise: Effects on Wagenmakers, A.J.M., Bechers, E.J., Brouns, F., Kuipers, H.,
metabolism and performance. Exercise and Sports Science Soeters, P.B., Van der Vusse, G.J. and Saris, W.H.M.
Reviews, 19, 1-40. (1991). Carbohydrate supplementation, glycogen
Davis, J.M., Bailey, S.P., Woods, J.A., Galiano, F.J., depletion, and amino acid metabolism during exercise.
Hamilton, M. and Bartoli, W.P. (1992). Effects of American Journal of Physiology, 260, E883-E890.
carbohydrate feedings on plasma free-tryptophan and Wilson, W.M. and Maughan, R.J. (1992). Evidence for a
branched-chain amino acids during prolonged cycling. possible role of 5-hydroxytryptamine in the genesis of
European Journal of Applied Physiology, 65, 513-519. fatigue in man: Administration of paroxetine, a 5-HT re-
Davis, J.M., Bailey, S.P., Jackson, D.A., Strasner, A.B. and uptake inhibitor, reduces the capacity to perform
Morehouse, S.L. (1993). Effects of a serotonin (5-HT) prolonged exercise. Experimental Physiology, 77,
agonist during prolonged exercise to fatigue in humans. 921-924.
Medicine and Science in Sports and Exercise, 25, S78. Young, S.N. (1986). The clinical psychopharmacology of
Enoka, R.M. and Stuart, D.G. (1992). Neurobiology of tryptophan. In Nutrition and the Brain (edited by R.J.
muscle fatigue. Journal of Applied Physiology, 72, Wurtman and J.J. Wurtman), Vol.7, pp. 49-88. New York:
1631-1648. Raven Press.