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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

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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

C 2008 The Author. Journal compilation C 2008 The Physiological Society


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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.



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