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Not a simple topic

‘Fatigue is multifactorial’ — it has diverse causes and many components, and expresses itself in varied ways. Even if we postpone discussion of mental fatigue, the purely physical dimensions of the word will prove more flexible than the first-time enquirer probably suspects. A hockey or rugby winger, after sprinting 60 metres, has to stop; but the fatigue experienced is of a palpably different kind from that at the end of a day's hill walking, yet alone a marathon race. Another sprint down the wing is possible within 1–2 minutes; another marathon is not possible that day. We will take these two extremes of sports fatigue, and related experiences, in that order. The entry on skeletal muscle should, however, be read first, and that on exercise may also be helpful.

‘Sprint’ fatigue

Very intensive exercise, such as that involved in sprinting, is powered predominantly by anaerobic metabolism. This form of metabolism produces lactic acid, and it is normally considered to be the acidity of this which stops muscles working. No form of fatigue has a single cause, but very intensive dynamic exercise probably comes nearer to being brought to an end by one mechanism than any other form of activity.

Degrees of acidity are expressed scientifically in terms of ph units, lower values indicating greater acidity. The pH within resting muscle cells is about 7.2. If it falls to around 6.4, which can happen after about a minute of really intensive activity in mammals and humans, the great majority of experiments indicate that both force-generation and further metabolism will be severely inhibited. (The musculature of salmon, after 30 seconds' swimming flat-out up a salmon ladder or striving to jump a weir, has been reported to touch pH 6.0; warm-blooded animals cannot tolerate this value.) Recovery from the major part of the fatigue is almost as rapid as onset. One of the few anomalies in the account is that the recovery of pH within the cells is not as quick. Also the inhibition of force-production by acidity is much more marked in experiments done on isolated muscles at the salmon's body temperature than at our own. So the mechanisms involved may be less direct than has long been thought, but the association between acidity and fatigue remains very strong.

Decline of speed and power

It is never more obvious than towards the end of a burst of sprinting that fatigue consists not only in loss of the force that muscles can produce but in impairment of their shortening speed. Since many actions in life depend not on either force or speed alone, but on power, which involves both, the effect of fatigue is redoubled. Power is the essence of such varied actions as a high jump, a javelin throw, a tennis serve, an axe-stroke, or work with a saw.

Isometric fatigue

Intensive isometric (static) exercise produces no power at all, since it causes no movement. Nevertheless, isometric fatigue has about the same time-scale as that of intense dynamic exercise, and near-complete recovery is also comparably fast. Build-up of acidity is part of the mechanism here, too, but there are other factors. Muscles exerting more than about a third of their maximum static force squeeze the intramuscular blood vessels so hard that they cut off their own blood supply: effectively they operate under a self-imposed tourniquet. This produces a more profound loss of force than sprinting. Our fit hockey winger, if she slowed down by 20–30% after her 60 metre dash, could go on running for many minutes. A maximal isometric contraction falls to half or less in the first minute, and starting at 70–80% maximum force retards the subsequent decline only a little. (Try applying your utmost effort to undoing a recalcitrant jar-top; maintaining it for more than 3–5 seconds is impossible.) Only when force has fallen to 10–15% of the original maximum does a steady state ensue which can be maintained for long periods, because only then has the muscle's self-tourniquet been fully released. Fortunately it is this level of force which muscles involved in posture need to maintain, when a guardsman stands to attention for long periods.

During self-tourniquet, muscles trap within themselves many products of contractile effort in addition to lactic acid. Perhaps the most important other product is potassium. Potassium ions come out of all electrically-active cells, including muscle fibres, in the second half of each electrical impulse (‘action potential’). Outside the muscle cells they probably contribute to fatigue in at least three ways. Firstly, they may lead to failures of impulse transmission down the finer motor nerve branches within the muscle, so fewer muscle fibres receive the instructions to go on contracting. Secondly, by accumulating particularly in the narrow ‘transverse tubules’, which have the function of conveying activation from the surface to the depth of each muscle fibre, they can block propagation of further impulses at that point; consequently the centre of the fibre may cease to produce force, even when the surface is still doing so. Thirdly, by depolarizing sensory nerve endings embedded in the interstitial spaces between muscle fibres, potassium ions are thought to contribute to the pain of sustained contraction, and to a number of other effects such as increased respiration and elevated blood pressure. An organic product of metabolism, adenosine, also probably contributes to the pain, and contrary to a common assumption it is almost certainly more significant in this than lactic acid.

Long-lasting activity

At the end of a day in the hills, or even a marathon race, muscle pH is not significantly lowered; the metabolism has been aerobic not anaerobic, so negligible lactic acid has been produced. The main causes of fatigue in these ‘endurance activities’ appear to be microscopic muscle damage, and simply running out of fuel.

The fuel concerned is glycogen, the animal body's stored carbohydrate. Untrained people have only enough glycogen for perhaps 6–10 km at a racing pace; athletes who are highly trained, and have loaded themselves with carbohydrate food for the last few days before a race, will normally reach the finish with just a little left. Without glycogen one is not immobile, but maximum speed drops severely. The explanation for this hinges on the fact that muscles are composed of different types of fibre. The fastest fibres can utilize only carbohydrate, and many others — perhaps, in human beings, all others — can work faster on carbohydrate than on their alternative fuel, fat. Ultramarathons, channel swims, and other competitive events lasting many hours have traditionally been performed almost entirely on fat. However, technology can alter this situation to some extent, and cyclists on such events as the Tour de France (who can carry drinking bottles easier than runners) take high-carbohydrate drinks throughout the day to ward off total depletion of their carbohydrate stores as long as possible; the drink keeps blood glucose concentration high, and the muscles can use the glucose direct or turn it into glycogen.

As to the micro-damage, this is often marked enough to see in electron micrographs of endurance runners' leg muscles, and might prove even more severe after strenuous climbs. However, a form of damage on a yet smaller scale probably affects the internal activating mechanism of every fibre in a profoundly fatigued muscle. Experimentalists have called this ‘low frequency fatigue’, for it shows as substantially subnormal force when the muscle is artificially stimulated at fairly low frequencies (mimicking gentle voluntary activation). High-frequency stimulation overcomes the shortfall, and voluntary ‘superhuman effort’ has the equivalent effect: presumably high rates of natural or artificial stimulation release, even from a somewhat damaged system, enough of the required agent, calcium ions, to activate the contraction fully.

Intermediate intensities

In running races from 1500 to 10 000 metres and cycling, swimming, or rowing events of similar duration, many of the mechanisms described thus far probably mingle. Lactic acid builds up, but more slowly than in a sprint; glycogen depletion may be significant in some of the fastest fibres, though not generally; calcium release is probably impaired in more than one way; and so on. One additional mechanism, however, may have its greatest importance in activities lasting from a few minutes to half an hour. The key biological energy-molecule, adenosine triphosphate (ATP), is broken down to adenosine diphosphate (ADP), hydrogen ions, and phosphate ions in the process of force-generation and then must be reconstituted by metabolism. Reconstitution seems to lag increasingly behind breakdown as exercise proceeds; significant concentrations of the breakdown products thus build up in intensively working muscle. In the events we are now considering this is especially true of phosphate ions. Hydrogen ions, when not also being released at great rate by the additional mechanism of anaerobic metabolism, are better ‘buffered’. The effects the two ions can have are discussed in the next section.

Action of ATP breakdown products

If two water tanks are linked at the bottom by a pipe, and one starts empty while the other is full, water at first flows into it rapidly; gradually, however, the build-up of water in the receiving tank slows down further flow between them. In rather the same way the build-up of the products of any chemical reaction weakens its forward drive. This is a key mechanism by which both hydrogen ions (acidity) and phosphate ions are generally thought to contribute to muscle fatigue. No doubt ADP would do so too, did not metabolism ensure that ADP concentration never rises far.

Muscle contraction is brought about by the concerted action of submicroscopic structures called ‘cross bridges’. Their power-generating strokes are weakened, and may also be individually slowed, when hydrogen and phosphate ions accumulate. In addition, in the majority of experimental conditions, hydrogen ions inhibit the amount of calcium released from intracellular stores by electrical excitation — which has the consequence that fewer cross-bridges are even active.

Notice that ‘running out of ATP’ does not appear among the mechanisms inducing fatigue. ATP concentrations are maintained quite close to resting value by muscle metabolism; evolution has ensured this, since to let them fall far could be fatal. The fatality would not be due to weakened contractions but to a single over-strong one: not fatigue but ‘rigor mortis’, the rigidity of death, is what sets in when ATP concentrations fall seriously low! So muscle fatigue is not due to an energy crisis in a direct, simple way, though some of the fatigue mechanisms we have discussed could be said to represent energy crises in broader senses.

Systemic fatigue

So far, all the mechanisms discussed have been of ‘muscle fatigue’, but the body can tire of prolonged work in other ways. Fluid loss, notably in sweat, is a major factor. Even 2–3% loss (1–2 litres, according to one's size) impairs performance. Thus sportspeople competing in hotter countries than their own should check themselves each morning for weight loss, which is likely to occur even without their being active. Heat in fact presents a double challenge, for blood is diverted from muscles to skin, so that it may be cooled there by evaporating sweat; when there is less fluid circulating, due to sweating, circulation in both regions is compromised. Furthermore if core temperature rises more than about 3°C, bodily and mental functions are seriously impaired, and heat stroke may set in. Thus the importance of maintaining fluid intake during prolonged activity, even in temperate climates and more so in hot ones, cannot be overstated; and it is unfortunate that thirst is an insufficient guide — in these circumstances we always need more fluid than the thirst mechanism indicates.

At the other extreme, cold is (in a purely arithmetical sense) even more dangerous than heat, for in many people core temperature need only fall 2°C to produce the severe impairments of physical and mental function characterizing hypothermia. This is a thermal risk associated with exercise in exposed conditions, though not due to it, and involving fatigue-like symptoms rather than fatigue itself. Furthermore, the best preventive on land, however wet the conditions, is to maintain activity; so hypothermia in these circumstances becomes not a cause but a consequence of fatigue. (In cold water, however, attempts to swim are counterproductive, for stirred water extracts body heat faster than muscle activity can generate it).

Irrespective of temperature, though more challenged by cold than heat, blood glucose must be maintained. If it is not, the organ that suffers worst is the brain, which can only operate on glucose fuel. About one fifth of the glycogen in a rested body is stored in the liver, not the muscles, and it is from there, as exercise goes on, that it is released into the blood as glucose. When this mechanism fails and blood glucose (‘blood sugar’) falls below about half its resting value, mental functions become seriously impaired.

The heart is a muscle, and both it and the muscles of breathing can in principle be subject to fatigue. When healthy people exercise at ordinary altitudes, however, neither of these categories of muscle fatigues sufficiently to impair the body's performance — though either heart or lung disease can alter this situation profoundly.

Central nervous fatigue

This may be regarded as the physiologist's name for what others would term ‘mental fatigue’; however, it carries the specific implication that a physical mechanism can be identified, which is not (or not yet?) the case in all mental fatigue.

A particularly interesting mechanism has recently been proposed, which would make central nervous fatigue a direct consequence of prolonged muscle activity. Muscles running short of carbohydrate fuel instead take up increased amounts of certain amino acids, notably the branched chain amino acids (BCAA) such as valine. Consequently, after a while, less of these remain in the blood than were present when the exercise began. Now, there is a transport mechanism across the walls of brain capillaries which normally shares out its services between BCAA and other large, uncharged amino acids — the most prominent being tryptophan. As muscle demands continue, less BCAA and instead more tryptophan is taken into the brain. The neurotransmitter substance serotonin (‘5-HT’) is made from tryptophan, so the consequence of the shift in uptake is that more serotonin is synthesized. The crux underlying all this is that increased brain concentrations of serotonin appear to promote the symptoms and sensation of fatigue.

Inverting the direction of brain–muscle interaction, every sports coach knows that psychology has profound effects on the most physical of performances; even shouts of encouragement can be crucial. Fatigue, however, occurs in more situations than those involving muscular effort. Can anything be said about the others? We all know that, when tired, we perform less well at both motor and mental tasks — indeed, the mental ones are often impaired earlier and more severely, so that physical exercise can be a fruitful way of throwing off mental fatigue. That there are physical aspects even to mental fatigue is strongly suggested when we recall that hunger or severe thirst, extremes of cold or heat, oxygen lack, alcohol, and other drugs can all increase fatigue — while drugs with the opposite effect, such as caffeine or amphetamines, can help ward it off. Altered levels of brain transmitters, particularly in regions of the brain stem — increased serotonin and acetylcholine, decreased noradrenaline — have been demonstrated in certain experimental studies of fatigue. But it is probably fair to say that scientific investigation is still only scratching the surface of the problem, as the most universal and ultimately irresistible cause of mental fatigue is lack of sleep. Despite the best efforts of committed researchers, we do not yet really understand sleep. Until we do, there seems little hope of comprehending what happens when we have had too little.

Neil Spurway


Gandevia, S. C. et al. (1996). Fatigue: neural and muscular mechanisms. Plenum, New York.
Newsholme, E. A.,, Blomstrand, E.,, and and Ekblom, B. (1992). Physical and mental fatigue: metabolic mechanisms and importance of plasma amino acids. British Medical Bulletin, 48, 477–95.
Wilmore, J. H. and and Costill, D. L. (2000). Physiology of sport and exercise. 2nd ed. Human Kinetics, Champaign, Illinois.

See also cold exposure; exercise; heat exposure; skeletal muscle.

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"fatigue." The Oxford Companion to the Body. . 25 Mar. 2017 <>.

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fatigue (in physiology)

fatigue, in physiology, inability to perform reasonable and necessary physical or mental activity. Muscle fatigue, for example, results when the contractile properties of muscle are reduced, and continued exertion is impossible unless the muscle is allowed to rest. In muscle tissue, the depletion of glycogen (stored glucose), a source of energy for muscle cells, and the accumulation of lactic acid, which is produced through the breakdown of glucose, was long thought to the cause of muscle fatigue, but it is now known that the lactic acid produced is used as an energy source as well. A new explanation of muscle fatigue suggests that it is related to the control of the flow of the calcium ions in muscle. The release of those ions causes muscle contraction, while their storage causes relaxation. After prolonged exercise, the channels that control calcium flow become leaky, diminishing the muscle cells ability to contract. In the normal body the damaged channels are repaired after a period of rest. There are some persons in whom fatigue is a chronic state that does not necessarily result from activity or exertion. In some instances this abnormal fatigue may be associated with systemic disorders such as anemia, a deficiency of protein or oxygen in the blood, addiction to drugs, increased or decreased function of the endocrine glands, or kidney disease in which there is a large accumulation of waste products. If excessive fatigue occurs over a prolonged period, exhaustion (marked loss of vital and nervous power) may result. In most persons with chronic fatigue, however, the condition seems to be associated with bipolar disorder. Thorough medical and psychiatric examination may be required.

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"fatigue (in physiology)." The Columbia Encyclopedia, 6th ed.. . 25 Mar. 2017 <>.

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"fatigue (in physiology)." The Columbia Encyclopedia, 6th ed.. . Retrieved March 25, 2017 from