Michael J.

McKenna and Mark Hargreaves

J Appl Physiol 104:286-287, 2008. First published Oct 25, 2007; doi:10.1152/japplphysiol.01139.2007
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J Appl Physiol 104: 286287, 2008;

doi:10.1152/japplphysiol.01139.2007.

Editorial

HIGHLIGHTED TOPIC

Fatigue Mechanisms Determining Exercise Performance

Resolving fatigue mechanisms determining exercise performance: integrative

physiology at its finest!
Michael J. McKenna1 and Mark Hargreaves2
1

Muscle Ions and Exercise Group, School of Human Movement, Recreation and Performance, Centre for Ageing,
Rehabilitation, Exercise and Sport, Victoria University, Melbourne; and 2Department of Physiology, The University
of Melbourne, Parkville, Victoria, Australia

Address for reprint requests and other correspondence: M. J. McKenna,

School of Human Movement, Recreation and Performance, Centre for Ageing,
Rehabilitation, Exercise and Sport, Victoria Univ., PO Box 14428, Melbourne,
8001 Victoria, Australia (e-mail: michael.mckenna@vu.edu.au).
286

importantly, within the central nervous system itself. Furthermore, fatigue can be understood not as a failure of regulation,
the bad guy, but as a highly regulated strategy conserving
cellular integrity, function and, indeed, survival. These stateof-the-art reviews reinforce the concept that understanding
fatigue is integrative physiology at its finest. Each review
integrates existing knowledge and importantly, includes a
focus on new directions for the field, ensuring each is obligatory reading for all interested in fatigue and exercise.
The first six reviews focus on the mechanisms and importance of what have been labeled as peripheral muscle fatigue
and central fatigue. The first two reviews have a cellular or
myo-site focus of fatigue. Drs. Allen, Westerblad, and Lamb
(1) review evidence for a failure of sarcoplasmic reticulum
Ca2 release as a major causative factor in fatigue in muscle.
The review draws heavily on elegant single-fiber experiments,
which have used intact or mechanically skinned fibers and
which clearly link insufficient Ca2 release to a reduction in
force. They focus on the role of inorganic phosphate sequestration of Ca2 within the sarcoplasmic reticulum, rather than
changes in action potential amplitude, as a primary factor
responsible for the fatigue-induced decline in cytosolic Ca2
concentration and force. Drs. McKenna, Bangsbo, and Renaud
(5) examine exercise effects on muscle ionic homeostasis and
their essential role in fatigue, integrating findings from human
exercise studies and in vitro studies of ionic effects on muscle
function. Marked intracellular-interstitial perturbations in K
and Na concentrations and impaired Na-K pump activity
are presented as causative factors in fatigue, via cellular membrane depolarization and inexcitability; whereas Cl conductance changes oppose these effects. Hence regulation of each
of these ions, and of the Na-K pump, must be considered in
understanding fatigue. The review by Drs. Secher, Seifert, and
van Lieshout (8) goes to the top end, investigating the role of
cerebral metabolism in fatigue. They show that exercise increases cerebral perfusion when perfusion is analyzed appropriately. Furthermore, arteriovenous studies across the brain
indicate that glucose and lactate uptake are increased with
exercise, but that cerebral oxygenation and cerebral metabolic
ratio [O2 uptake/(glucose and 12lactate uptake)] are in fact
decreased. As a consequence, oxygenation of the brain is
challenged during exercise and may be a vital factor in what
has been defined as central fatigue.
Continuing the focus on the central nervous system, Drs.
Taylor and Gandevia (9) review the supraspinal and spinal
mechanisms contributing to fatigue during both maximal and
submaximal voluntary contractions. They summarize results

8750-7587/08 $8.00 Copyright 2008 the American Physiological Society

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THE ORIGINS OF FATIGUE during exercise have intrigued scientists

for well over a century and have proven to be a rich, but
complex, area of investigation. Understanding fatigue and the
consequent exercise limitation is not just an intellectual curiosity, but has far-reaching implications that traverse the broad
spectrum of our communities. In chronically diseased or
acutely ill patients, fatigue and exercise limitation can profoundly restrict daily activities and thus impair quality of life.
In healthy individuals, fatigue can restrict performance in
diverse occupational duties such as firefighting, the military,
construction, and laboring, as well as limiting participation in
recreational activities and sports. Most readers would link
fatigue and exercise limitation to the grand stage of national
and international sporting competition, adversely affecting
elite athletic performance, with implications for medals, glory,
and the sports industry. Fatigue and exercise limitation also
impact on the young through to the aged, thus affecting all
persons at multiple stages of our lives. It is therefore not
surprising that investigation into the underlying causes of
fatigue and exercise limitation has attracted special attention of
scientists from clinical, basic, and applied science specializations.
Early investigations on fatigue mechanisms focused on metabolic fuel availability or accumulation of waste products.
Prolonged exercise was thus considered to be limited by
reduced muscle glycogen availability and/or hypoglycemia.
Fatigue during intense exercise was typically portrayed as a
consequence of phosphocreatine depletion and lactic acidosis.
With evidence that action potential transmission across the
neuromuscular junction was not impaired, fatigue was ascribed
as largely occurring within the active muscles. Hence, the term
muscle fatigue is now firmly entrenched within the general
scientific vocabulary. This series of nine mini-reviews, all by
experts in their respective fields, first demonstrate the tremendous recent advances in understanding the complex phenomenon known as fatigue. Second, these reviews clearly indicate
that fatigue rather than muscle fatigue is much more
appropriate for voluntary exercise, since fatigue limiting exercise involves mechanisms within the contracting peripheral or
locomotive muscles and encompasses the respiratory muscles,
muscle perfusion, other inactive skeletal muscle and organs
regulating fuel, metabolite, or ionic homeostasis and, most

Editorial
287

J Appl Physiol VOL

supply exacerbates the development of fatigue via direct effects on both muscular performance and central nervous system motor activation and via inhibitory feedback from those
muscles affected by reduced oxygen delivery. Finally, Drs.
Romer and Polkey (7) provide an overview of the role of
respiratory muscles in exercise limitation. Long considered the
loyal servant of the cardiovascular and musculoskeletal systems during exercise, there is clear evidence that in certain
exercise conditions, respiratory muscle fatigue occurs and can
limit arterial oxygenation, with consequent effects on muscular
and nervous system function (see Ref. 2). Furthermore, reflexes arising from fatigued respiratory muscles act to limit
blood blow to active limb muscle, but in so doing enhance limb
muscle fatigue and reduce exercise tolerance. These latter
reviews elegantly demonstrate the critical interdependence
between central and peripheral mechanisms in the development
of fatigue and exercise limitation.
So how then do we understand this complex phenomenon
known as fatigue? Clearly, fatigue during exercise can be
viewed as a cascade of events occurring at multi-organ, multicellular, and at multi-molecular levels. The challenge for scientists is to understand how these mechanisms work together.
The implications are profound as fatigue is important in exercise limitation, affects the whole of the community, and thus
impacts on human health, economics, and sporting endeavors.
Finally, all reviews include topics for future research, ensuring
this series will have broad appeal and continuing impact.
REFERENCES
1. Allen DG, Lamb GD, Westerblad H. Impaired calcium release during
fatigue. J Appl Physiol (October 25, 2007). doi:10.1152/japplphysiol.
00908.2007.
2. Amann M, Calbet JAL. Convective oxygen transport and fatigue. J Appl
Physiol (October 25, 2007). doi:10.1152/japplphysiol.01008.2007.
3. Ferriera L, Reid MB. Redox modulation of muscle fatigue. J Appl
Physiol; doi:10.1152/japplphysiol.00953.2007.
4. Fitts R. Cross bridge mechanisms of fatigue. J Appl Physiol. In press.
5. McKenna MJ, Bangsbo J, Renaud JM. Muscle K, Na, Cl disturbances and Na-K pump inactivation: implications for fatigue. J Appl
Physiol (October 25, 2007). doi:10.1152/japplphysiol.01037.2007.
6. Nybo L. Hyperthermia and fatigue. J Appl Physiol (October 25, 2007).
doi:10.1152/japplphysiol.00910.2007.
7. Romer L, Polkey MI. Respiratory muscle function during exercise and
fatigue. J Appl Physiol; doi:10.1152/japplphysiol.01157.2007.
8. Secher NH, Seifert T, van Lieshout JJ. Cerebral metabolism and fatigue.
J Appl Physiol; doi:10.1152/japplphysiol.00853.2007.
9. Taylor J, Gandevia S. Central aspects of fatigue in submaximal contractions. J Appl Physiol; doi:10.1152/japplphysiol.01053.2007.

104 JANUARY 2008

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from elegant experiments in human volunteers that use twitch

interpolation and transcranial magnetic stimulation to probe the
relative importance of central and peripheral fatigue mechanisms. While maximal contractions have been studied the
most, and it is technically challenging to study submaximal
contractions, there is evidence of central fatigue in both types
of muscle activation. Returning to the muscle, Dr. Fitts (4)
examines the role of cross-bridge cycling in the development
of fatigue. There are numerous metabolic factors with the
potential to impair cross-bridge interactions and they are well
discussed. The role of acidosis has been debated over the years
and new results suggest an inhibitory effect of increased [H]
on muscle fiber shortening velocity and power production (4).
The past decade has seen an explosion of interest in reactive
oxygen species (ROS) and their impact on skeletal muscle
function. Drs. Ferriera and Reids review (3) identifies increased ROS production in contracting muscles as a cause of
fatigue in a variety of experimental models. The intracellular
target proteins are not fully resolved, but likely include tropomyosin, myosin, actin, Ca2-ATPase, and Na-K-ATPase,
with thiol oxidation strongly implicated as a key player. In a
new twist, they address the important question of whether
antioxidants can delay fatigue, by primarily focusing on studies
using the non-specific antioxidant N-acetylcysteine (NAC) and
with impact on the abundant intracellular antioxidant glutathione. They demonstrate that NAC is efficacious in both exercising humans and in vitro preparations.
The final three reviews examine applied integrative aspects
of fatigue, covering hyperthermia (6), arterial oxygenation (2),
and respiratory muscle function during exercise (7). Dr. Nybo
(6) heats up the debate as he eloquently outlines the importance
of hyperthermia-induced fatigue, contrasting mechanisms of
exercise limitation during intense and prolonged exercise in
humans. Cardiovascular limitations to high-intensity exercise
performance with hyperthermia are apparent, with declines in
cardiac output, muscle blood flow, and oxygen uptake. Hyperthermia during prolonged exercise is associated with a reduction in central activation, or central fatigue, which is progressive rather than an all-or-none phenomenon. Interestingly,
Nybo also challenges the concept of a critical core temperature at which exercise cessation must occur in voluntary
exercise. Convective oxygen transport has long been known to
be a critical determinant of maximal oxygen uptake and exercise performance. Drs. Amman and Calbet (2) review the
effects of oxygen availability on fatigue development and
exercise performance, concluding that a reduction in oxygen