1030

Exp Physiol 93.9 pp 10301033

Experimental Physiology Historical Perspective

Celebrating 100 years of publishing discovery in physiology

DOI: 10.1113/expphysiol.2007.039032

2008 The Author. Journal compilation

2008 The Physiological Society

Downloaded from Exp Physiol (ep.physoc.org) by guest on January 24, 2013

Exp Physiol 93.9 pp 10301033

The mechanism of voluntary muscle fatigue

1031

Experimental Physiology Historical Perspective

Voluntary muscle strength and endurance: The mechanism of voluntary muscle fatigue by 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; rst 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: s.gandevia@unsw.edu.au

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 to their operation have long 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 difculties 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 muscular fatigue (Reid, 1928) implies that there is a single 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 signies a reduction in maximal exion movement of the middle nger produced by voluntary exercise. This model was popularized by Angelo Mosso
C

in the late 1880s. He had developed an ergograph which recorded the changing position of the nger during isotonic contractions of the nger exor 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 bres? Despite the length of Reids paper, 25 pages with 20 gures, 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 rst paragraph launches 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 we now 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 upper arm proximal to 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. The two-page Summary and Conditions section which completes the manuscript derives largely from the human studies.

Some key ndings

What are the main ndings that Reid emphasized? First, he claimed that articial repetitive stimulation over the median nerve or stimulation more distally (presumably activating intramuscular nerves at the socalled 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 with articial stimulation, 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 qualied, 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 in most 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 with technical problems, the main one 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 reected 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 response as 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 fulls the exact denition 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

2008 The Author. Journal compilation

2008 The Physiological Society

Downloaded from Exp Physiol (ep.physoc.org) by guest on January 24, 2013

1032 muscle fatigue. A muscle exhausted by electrical stimulation failed to generate force 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 minutes of repetitive use (e.g. Vagg et al. 1998). Hence, he found the stimulus intensity had to be sufcient. His exhortation not to use inadequate articial excitation 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 are excited by the stimulus postexercise. 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 peripheral axonal changes were not critical for muscle fatigue. Third, the task modied 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 difculties in assessment of central fatigue in lowforce 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 ow, generate the supraspinal changes associated with central fatigue (Smith et al. 2007). Fourth, the performance in volitional tasks was inuenced by a putative inhibiting inuence 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 produced by a cuff inated above arterial pressure, central fatigue in voluntary contractions developed more quickly. Reid must have been well aware of the high level of muscle pain that develops during repetitive

S. C. Gandevia voluntary contractions under ischaemic conditions. The idea that something arising in the muscle limited performance was (and still is) hard to deny. What this is and how it inuences the spinal and supraspinal circuitry concerned with the motor output remain challenges that still motivate current research. Interestingly, Reid appreciated that there 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 the concept 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 on many 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 bre relaxation after rapid repetitive contractions, the effect of partial occlusion of the circulation during muscle contractions and the role of lactate in muscle fatigue.

Exp Physiol 93.9 pp 10301033

Some technical considerations

Many methodological questions come with reassessment of an 80-year-old paper. Some cannot be easily claried now, such as details of the stimulus pulses and location of electrodes, but two others merit mention. Finger exion involves two extrinsic nger exors as well as interossei and lumbricals. Any nger myograph must ensure adequate stabilization at the wrist in both exionextension 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 sufcient charge to drive the sarcolemma directly (i.e. muscle activation beyond the neuromuscular junction) and so claims that muscles are driven without involvement of intervening nerve is unjustied.

More recent developments

If Reid were to examine subsequent research in the eld, what might he nd interesting? One of our results directly supports his view
C

that in some of the conditions he studied there was fatigue not only at a muscle bre level, but also direct central fatigue within the brain, plus an inhibitory effect produced by a reex-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 subcortical stimulation of the descending corticospinal tract) during and after a maximal voluntary isometric contraction of the elbow exors has revealed activity-induced changes at the motor cortex (e.g. Gandevia et al. 1996), the corticomotoneuronal synapse (Gandevia et al. 1999) and the motoneurone (Butler et al. 2003). Cortical stimulation can 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 compound electromyographic response and the cortical silent period lengthens, often by more than 50 ms (Taylor et al. 1996). However, if a cuff is inated 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. By contrast, the supraspinal fatigue fails to recover until the circulation is restored (Gandevia et al. 1996). The peripheral muscle 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.
C

2008 The Author. Journal compilation

2008 The Physiological Society

Downloaded from Exp Physiol (ep.physoc.org) by guest on January 24, 2013

Exp Physiol 93.9 pp 10301033

The mechanism of voluntary muscle fatigue

Enoka RM & Stuart DG (1992). Neurobiology of muscle fatigue. J Appl Physiol 72, 16311648. Gandevia SC (2001). Spinal and supraspinal factors in human muscle fatigue. Physiol Rev 81, 17251789. Gandevia SC, Allen GM, Butler JE & Taylor JL (1996). Supraspinal factors in human muscle fatigue: evidence for suboptimal output from the motor cortex. J Physiol 490, 529536. Gandevia SC, Petersen N, Butler JE & Taylor JL (1999). Impaired response of human motoneurones to corticospinal stimulation after voluntary exercise. J Physiol 521, 749759. Herbert RD & Gandevia SC (1999). Twitch interpolation in human muscles: mechanisms and implications for measurement of voluntary activation. J Neurophysiol 82, 22712283. Hunter SK, Duchateau J & Enoka RM (2004). Muscle fatigue and the mechanisms of task failure. Exerc Sport Sci Rev 32, 4449. Johnson KV, Edwards SC, Van Tongeren C & Bawa P (2004). Properties of human motor units after prolonged activity at a constant ring rate. Exp Brain Res 154, 479487. Kouzaki M & Shinohara M (2006). The frequency of alternate muscle activity is associated with the attenuation in muscle fatigue. J Appl Physiol 101, 715720. Marsden CD, Meadows JC & Merton PA (1983). Muscular wisdom that minimizes fatigue during prolonged effort in man: peak rates of motoneuron discharge and slowing of discharge during fatigue. Adv Neurol 39, 169211. Merton PA (1954). Voluntary strength and fatigue. J Physiol 123, 553564. Merton PA (1956). Problems of muscular fatigue. Br Med Bull 12, 219221. Nordstrom MA, Gorman RB, Laouris Y, Spielmann JM & Stuart DG (2007). Does motoneuron adaptation contribute to muscle fatigue? Muscle Nerve 35, 135158.

1033
Reid C (1928). The mechanism of voluntary muscular fatigue. Q J Exp Physiol 19, 1742. Smith JL, Martin PG, Gandevia SC & Taylor JL (2007). Sustained contraction at very low forces produces prominent supraspinal fatigue in human elbow exor muscles. J Appl Physiol 103, 560568. Taylor JL, Butler JE, Allen GM & Gandevia SC (1996). Changes in motor cortical excitability during human muscle fatigue. J Physiol 490, 519528. Taylor JL & Gandevia SC (2008). A comparison of central aspects of fatigue in submaximal and maximal voluntary contractions. J Appl Physiol 104, 542550. Todd G, Butler JE, Taylor JL & Gandevia SC (2005). Hyperthermia: a failure of the motor cortex and the muscle. J Physiol 563, 621631. Todd G, Taylor JL, Butler JE, Martin PG, Gorman RB & Gandevia SC (2007). Use of motor cortex stimulation to measure simultaneously the changes in dynamic muscle properties and voluntary activation in human muscles. J Appl Physiol 102, 17561766. Todd G, Taylor JL & Gandevia SC (2003). Measurement of voluntary activation of fresh and fatigued human muscles using transcranial magnetic stimulation. J Physiol 551, 661671. Vagg R, Mogyoros I, Kiernan MC & Burke D (1998). Activity-dependent hyperpolarization of human motor axons produced by natural activity. J Physiol 507, 919925.

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 ndings 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 reex and cognitive levels.
References Adrian ED & Bronk DW (1929). The discharge of impulses in motor nerve bres: Part II. The frequency of discharge in reex and voluntary contractions. J Physiol 67, 119151. Amann M & Dempsey JA (2008). Locomotor muscle fatigue modies central motor drive in healthy humans and imposes a limitation to exercise performance. J Physiol 586, 161173. Butler JE, Taylor JL & Gandevia SC (2003). Responses of human motoneurons to corticospinal stimulation during maximal voluntary contractions and ischemia. J Neurosci 23, 1022410230. Enoka RM & Duchateau J (2008). Muscle fatigue: what, why and how it inuences muscle function. J Physiol 586, 1123.

Acknowledgements The authors research is supported by the National Health and Medical Research Council.

2008 The Author. Journal compilation

2008 The Physiological Society

Downloaded from Exp Physiol (ep.physoc.org) by guest on January 24, 2013