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1030 Exp Physiol93.9 pp 10301033
Experimental Physiology Historical Perspective
Celebrating 100 years of publishing discovery in physiology
DOI: 10.1113/expphysiol.2007.039032 C 2008 The Author. Journal compilation C 2008 The Physiological Society
) by guest on January 24, 2013ep.physoc.orgDownloaded from Exp Physiol (
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Exp Physiol93.9 pp 10301033 The mechanism of voluntary muscle fatigue 1031
Experimental Physiology Historical Perspective
Voluntary muscle strengthand endurance: The mechanism
of voluntary muscle fatigueby Charles Reid
Simon C. Gandevia
Prince of Wales Medical Research Institute
and University of New South Wales, Sydney,
NSW 2031, Australia
(Received 7 March 2008; accepted after
revision 20 March 2008; first published online
16 July 2008)
Corresponding author S. C. Gandevia:
Prince of Wales Medical Research Institute
and University of New South Wales, Sydney,
NSW 2031, Australia.
Email: [email protected]
Background
The brain drives muscle contractions to
support our posture and generate all our
movements. Not surprisingly, the neural
control of these vital processes and the
limits totheir operationhavelong fascinated
physiologists. How does the brain drive
motoneurones, the output of which then
generates a reasonably predictable muscle
force? If we can no longer perform a
repetitive or sustained task, such as typing
this article or lifting a suitcase, is the
limit in the muscle, or in one or more of
the many proximal steps from within the
brain, then along central and peripheral
conducting systems to within the muscle?
The natural intrusion of these physical
difficulties into our everyday activities has
doubtless fueled the physiologists desire
to understand them. Our intuition has
fooled us into thinking that the answers are
necessarily simple.
The bold title of Charles Reids important
paper The mechanism of voluntary muscularfatigue (Reid, 1928) implies that there is asingle mechanism. Not so. His results and
much subsequent work reveal that more
than one mechanism is at play and that
different mechanisms may predominate
under particular physiological conditions.
What does Reid mean by voluntary
muscular fatigue? It signifies a reduction in
maximal flexion movement of the middle
finger produced by voluntary exercise. This
model was popularized by Angelo Mosso
in the late 1880s. He had developed an
ergograph which recorded the changing
position of the finger during isotonic
contractions of the finger flexor muscles.
However, vigorous debate surrounded what
limited performance in this task: was it
limited by the intrinsic properties of the
muscles themselves, or by the central
nervous system and its capacity to deliver
impulses to the muscle fibres?
Despite the length of Reids paper,
25 pages with 20 figures, no history of the
debate is provided, presumably because
it was well known, being covered in
most contemporary textbooks. With no
formal background to the topic under
investigation, the papers first paragraphlaunches straight into Method in the
human subject. No details are given about
the type or number of subjects studied,
nor had we reached the era requiring
studies to be conducted according to
the Declaration of Helsinki on ethical
principles for medical research involving
human subjects. Reid claimed initially that
his aim was to examine movements when
the muscle was contracting practically
isometrically, a condition little studied
previously, but one in which he was
concerned (needlessly, as wenow know)that
limited muscle shortening implied limited
contraction of the active muscles. What
follows is a more comprehensive assessment
of muscle performance under isotonic and
quasi-isometric conditions, with normal
perfusion of the muscle and also during
ischaemia produced by a ligature on the
upperarm proximalto the forearm muscles.
Different fatigue protocols were evaluated.
For the most part, human subjects were
used, but studies were also conducted in
anaesthetized rabbits and pithed frogs. Thetwo-page Summary and Conditions section
which completes the manuscript deriveslargely from the human studies.
Some key findings
What are the main findings that Reid
emphasized? First, he claimed that artificial
repetitive stimulation over themedian nerve
or stimulation more distally (presumably
activating intramuscular nerves at the so-
called motor point) could produce no
marked difference in mechanical output
(weight lifted and moved, or isometric
force) in a maximal voluntary effort.
Hence, at least at the onset of these
efforts, the muscle output was limited to
the maximal output from the peripheral
muscle. Previous attempts by Mosso and
others had failed to generate such high
forces withartificialstimulation, which Reid
attributed to their likely use of submaximal
stimulation. We can now quantify precisely
voluntary activation of muscles. Formally,
this is the level of voluntary drive during
an effort and, unless qualified, the term
does not differentiate between drive to
the motoneurone pool and to the muscle
(Gandevia, 2001). Voluntary activation of
muscles is high during maximal efforts inmost able-bodied subjects for most (but
not all) muscles provided subjects receive
appropriate feedback of performance (for
review see Gandevia, 2001). We know
voluntary activation is high from correct
use of a twitch interpolation procedure,
in which the mechanical response to a
single supramaximal stimulus is measured
during maximal isometric efforts (Herbert
& Gandevia, 1999), rather than from
comparison of maximal tetanic and
voluntary forces. Despite its enticing
simplicity, the latter comparison is fraught
withtechnical problems,the mainone being
that nerve stimulation rarely, if ever, excites
just the axons active in the voluntary task.
Merton (1954) and others tried this in
the 1950s with a similar result to Reid,
but he and his colleagues later rightly
acknowledged this reflected a fortuitous
cancellation of technical errors (Marsden
et al. 1983).
Second, after repetitive lifting of a weight
until it could no longer be elevated
by voluntary means, nerve stimulation
produced a mechanical response. Reid
recognized the presence of the responseas the hallmark indicating the primarily
central nature of voluntary fatigue. In
his subject(s), Reid had found a progressive
reduction in the capacity to drive the
muscle fully during exercise; such a change
fulfils the exact definition of central
fatigue (Gandevia, 2001). Reid correctly
surmised that the production of force
by stimulation when volition had failed
eliminated the muscle (and myo-neural
junction) as a singular cause of voluntary
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1032 S. C. Gandevia Exp Physiol93.9 pp 10301033
muscle fatigue. A muscle exhausted by
electricalstimulation failed to generateforce
volitionally, but the converse did not hold;
a muscle exhausted by volition had some
response to peripheral stimulation. With
hindsight, Reid almost certainly realised
that the threshold for activation of motor
nerve axons had increased after minutesof repetitive use (e.g. Vagg et al. 1998).
Hence, he found the stimulus intensity had
to be sufficient. His exhortation not to
useinadequateartificialexcitation deserves
emphasis. If submaximal intensities are
used, the presence of activity-induced
hyperpolarization of motor axons means
that any peripheral components to fatigue
will be overestimated because fewer axons
areexcited by thestimuluspostexercise.Reid
argued that the return of volitional strength
to its prefatigued level, when the response
to submaximal nerve stimulation had not
yet recovered, suggested that any peripheralaxonal changes were not critical for muscle
fatigue.
Third, the task modified the results.
With small loads and lower contraction
rates, the fatigue was less obvious at
a peripheral level. Isometric contractions
altered quantitatively the results, but
evidence for a combination of central and
peripheral fatigue in maximal efforts was
strong. The subtleties of the central factors
in task dependence of fatigue have been
emphasized in many studies by Enoka
and colleagues (for review see Enoka &
Stuart, 1992; Hunter et al. 2004; Enoka
& Duchateau, 2008), and the difficulties
in assessment of central fatigue in low-
force contractions have also been noted
(e.g. Taylor & Gandevia, 2008). Even very
weak isometric efforts, well below the level
conventionally thought to impede overall
muscle blood flow, generate the supraspinal
changes associated with central fatigue
(Smith et al. 2007).
Fourth, the performance in volitional taskswas influenced by a putative inhibiting
influence on the central nervous system
arising from afferent nervous impulses.The evidence for this is not unequivocal,
but Reid noted that central fatigue was
less evident if the voluntarily fatigued
muscles were rested compared with when
they continued to contract with peripheral
stimulation. Further, under ischaemic
conditions producedby a cuff inflated above
arterial pressure,centralfatiguein voluntary
contractions developed more quickly. Reid
musthavebeenwellawareofthehighlevelof
muscle pain that develops during repetitive
voluntary contractions under ischaemic
conditions. The idea that something arising
in themuscle limited performance was (and
still is) hard to deny. What this is and
how it influences the spinal and supraspinal
circuitry concerned with the motor output
remain challenges that still motivate current
research.Interestingly,Reid appreciatedthatthere were likely to be changes in the central
nervous system, independent of the effects
of afferent impulses. This he termed direct
central fatigue. He introduced this concept
in a footnote,and perhaps theconcept could
now be re-used. As an example, changes in
the active motoneurones due to repetitive
activation reduce their gain, a phenomenon
that makes it subjectively harder to drive
low-threshold motoneurones at a constant
rate and causes the output to the whole
motoneurone pool to rise (Johnson et al.
2004; see also Nordstrom et al. 2007).
Reids comprehensive study touches onmany other controversial issues in muscle
physiology; these include the effects of
synchronous and asynchronous stimulation
on force output, the tonic force secondary
to slowed muscle fibre relaxation after rapid
repetitive contractions, the effect of partial
occlusion of the circulation during muscle
contractionsandtheroleoflactateinmuscle
fatigue.
Some technical considerations
Many methodological questions come with
reassessment of an 80-year-old paper.
Some cannot be easily clarified now, such
as details of the stimulus pulses and
location of electrodes, but two others
merit mention. Finger flexion involves two
extrinsic finger flexors as well as interossei
and lumbricals. Any finger myograph
must ensure adequate stabilization at
the wrist in both flexionextension and
pronationsupination, or unintended and
unmeasured factors may come into play
(e.g. Kouzaki & Shinohara, 2006). Also,
electrical stimulation over human muscles
is unlikely to carry sufficient charge todrive the sarcolemma directly (i.e. muscle
activation beyond the neuromuscular
junction) and so claims that muscles are
driven without involvement of intervening
nerve is unjustified.
More recent developments
If Reid were to examine subsequent research
in the field, what might he find interesting?
Oneof ourresults directly supports his view
that in some of the conditions he studied
there was fatigue not only at a muscle
fibre level, but also direct central fatigue
within the brain, plus an inhibitory effect
produced by a reflex-like input from the
exercising muscles. Such a view of fatigue
was not popular among the physiologists
of the 1950s such as Pat Merton (1956)who propounded that anyone with a
sphygmomanometer and an open mind can
readily convince himself that the site of
this fatigue is in the muscles themselves.
The use of transcranial stimulation of
the motor cortex (as well as subcorticalstimulation of the descending corticospinal
tract) during and after a maximal voluntary
isometric contraction of the elbow flexors
has revealed activity-induced changes at
the motor cortex (e.g. Gandevia et al.
1996), the corticomotoneuronal synapse
(Gandevia etal. 1999)and the motoneurone
(Butler et al. 2003). Cortical stimulationcan even reveal the dynamics of muscle
contraction/relaxation and simultaneous
voluntary activation changes during the
electromyographic silence that follows the
stimulus (e.g. Todd et al. 2003, 2005,
2007). During a sustained maximal effort,
the force increment to a single cortical
stimulus is initially small, but increases
progressively (from 1 to 10% maximal
force). This is supraspinal fatigue (a
subset of central fatigue) in which the
motor cortical stimulus progressively gets
more from the cortex than volition
can harness. Reids direct changes also
occur in excitability of cortical circuitry.
The cortical stimulus produces an increased
compoundelectromyographicresponse and
the cortical silent period lengthens, often
by more than 50 ms (Taylor et al. 1996).
However, if a cuff is inflated proximal
to the exercising muscle and the subject
relaxes, after about 30 s rest, the response
to the motor cortical stimulus in a
new maximal effort has recovered. Bycontrast, the supraspinal fatigue fails to
recover until the circulation is restored
(Gandevia et al. 1996). The peripheralmuscle twitch too cannot recover during
ischaemia. The parsimonious explanation
is that motor cortical (and probably
motoneurone) function recovers quickly
from the repetitive activity in this isometric
exercise, but recovery of the capacity to
drive the motor cortex fully requires the
muscle circulation to remove the stimulus
to group IV muscle afferents and thus to
remove their inhibitory effect on voluntary
output.
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Exp Physiol93.9 pp 10301033 The mechanism of voluntary muscle fatigue 1033
The legacy
Reid leaves a rich legacy of experimental
approaches and conceptual advances, even
if we cannot quite repeat the experiments
as he performed them. This contribution
is all the more telling because his studies
preceded the development of single motor
unit recordings (Adrian & Bronk, 1929)and many of the classical Sherringtonian
views of spinal cord physiology. Even now,
controversies surround the translation of
the sorts of findings discussed here on hand
muscles contracting for short periods to
understanding the effects of sensory input
from fatiguing muscle on central drive
involved in whole-body exercise lasting
many minutes or hours (e.g. Amann &
Dempsey, 2008). For this, it seems that the
peripheral state of the muscle is monitored
by the central nervous system and used to
regulate motor output at both reflex andcognitive levels.
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Acknowledgements
Theauthors research is supportedby the National
Health and Medical Research Council.
C 2008 The Author. Journal compilation C 2008 The Physiological Society
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