muscle fatigue r. h. edwards138 r. h. t. edwards musclefunctionarelikely to becomemoreimportant in...

Postgraduate Medical Journal (March 1975) 51, 137-143.

Muscle fatigue

R. H. T. EDWARDSB.Sc., Ph.D., M.B., M.R.C.P.

Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London

SummaryMuscle fatigue is a common symptom but there are nouniversally accepted methods for quantitating thefunction of voluntary muscle. This paper describesthree main methods of assessment: simple clinical testsof muscle function; thermal probe measurements ofmetabolic heat production during muscular contrac-tion; needle biopsy studies of muscle structure andchemistry. These methods, though at a relatively earlystage of development, have given promising resultswhich suggest that they could be useful in assessing pos-sible new forms of treatment in patients with neuro-muscular disorders.

A SKELETAL muscle is said to be fatigued when it failsto sustain the required force. The mechanisms con-trolling the force of contraction in man involveseveral interrelated physiological and psychophysicalfeedback control mechanisms (Fig. 1). The systemof weakness and fatigue would seem likely in someway to stem from disturbances in these complexmechanisms. The physiology of fatigue has beenstudied at various levels of organization in animalmuscle preparations (reviewed in Simonson, 1971)but there have been few advances which would allowa systematic investigation of human weakness andfatigue. Electromyography and allied electrophysio-logical techniques play an increasingly importantrole in the clinical diagnosis of neuromuscular dis-orders (Desmedt, 1973) but still the evaluation is to alarge extent qualitative since quantitative EMG tech-niques, though potentially valuable, are still in theirinfancy.The assessment of weakness and fatigue by the

usual clinical examination of the neuromuscularsystem is difficult unless changes are gross. TheMedical Research Council grading scale for classify-ing muscular contraction has been widely used sinceits introduction during the Second World War(Medical Research Council, 1943). This scale, thoughvaluable for describing large changes, does not givea sufficiently objective assessment to allow precise

Based on a British Postgraduate Medical Federation'Scientific Basis of Medicine' Lecture, 1974.Correspondence: Dr R. H. T. Edwards, Royal Post-

graduate Medical School, Hammersmith Hospital, Du CaneRoad, London W12 OHS.

FIG. 1. Simple diagram of physiological and psycho-physical feedback mechanisms controlling muscularcontraction.

comparisons to be made on separate occasions bythe same observer or by different observers. A simplequantitative test, which might be included in theclinical examination,- is to time how long the patientwhen lying supine can hold one leg at 450 above thecouch. Normal subjects vary widely in the time theycan do this but the lower limits found in 150 menand 150 women by Fessel, Taylor and Johnson (1970)were 60 sec for the men and 30 sec for the women.A similar test, studied by the same authors, is totime how long the head can be held off the couch,when the subject is lying supine. Lower normal limitsfound in the same populations were 90 sec for themen and 30 sec for the women.

Voluntary, muscle power can now be quantitatedin the course of the usual examination of the neuro-muscular system with a new hand-held clinicaldynamometer (Edwards and McDonnell, 1974).This instrument ('The Hammersmith Myometer')fits into the palm of the examiner's hand and registersthe maximum force exerted on the patient's limbwhen a resisted movement is overcome. Clearly theforce recorded depends on the mechanics of themuscle and lever systems operating. The myometerhas to be applied to specified anatomical sites formeasurements to be consistent. This instrument ispotentially as useful an addition to the physicians'examination equipment as the sphygmomanometerand peak flow meter. Simple quantitative tests of

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138 R. H. T. Edwards

muscle function are likely to become more importantin the future since there is increasing emphasis onphysiotherapeutic methods in rehabilitation and thepromise of effective treatment of a number oflocomotor disorders as a result of recent advancesin neuropharmacology.Such simple clinical tests can never elucidate the

cause of fatigue. Moreover the measurement ofvoluntary contractions depends on the co-operationof the patient. The new approaches that I havesoughtto develop with my colleagues Dr D. K. Hill, F.R.S.,Dr D. A. Jones and Mrs Caroline Maunder at theRoyal Postgraduate Medical School are designed toovercome these problems and to break into thecomplex of interrelated servo-controls by establishingobjective measurements of the metabolic activity ofthe contracting muscle. Fortunately fatigue is asymptom (unlike angina) which can be experiencedunder experimental conditions by healthy individuals(e.g. after muscular exercise). It has, therefore, beenpossible to develop the approach by studies in healthyvolunteers before seeking possible application forthe study of patients with myopathies.

First a suitable muscle must be chosen for theexperimental studies. No muscle is ideal for thispurpose but the quadriceps has the advantages thatit is an important muscle for physical activities ineveryday life, and it is affected to a greater or lesserextent in many myopathies. Further advantages arethat the muscle (the vastus lateralis fraction of thequadriceps) is large enough and free of importantblood vessels and nerves to allow probes to be in-serted and for small samples of muscle to be safelytaken by a needle biopsy technique (Bergstrom,1962).In normal life a muscle may shorten, lengthen or

may remain at constant length during contraction.The first two forms of contraction are involved inrhythmic. ('dynamic') exercise, such as walking orcycling whereas the last ('isometric') form is impor-tant in gripping or holding tasks. An isometric con-traction of the quadriceps is studied with the subjectseated in an adjustable chair. The pelvic girdle isstabilized with a seat belt and the force of contrac-tion measured with a strain gauge attached to the

ankle when the knee is flexed to a right angle (Torn-vall, 1963). Intramuscular pressure rises and occludesthe muscle circulation at forces greater than 20% ofa maximum voluntary contraction (Barcroft andMillen, 1939; Edwards, Hill and McDonnell, 1972).This means that the energy for sustaining a long sub-maximal contraction must be almost entirely suppliedfrom anaerobic sources (Table 1). Since no externalwork is done in this type of contraction, all thechemically stored energy which is exchanged duringmuscular activity has to appear as heat, which in theabsence ofblood flow is largely retained in the muscle.The quadriceps muscle thus behaves as a 'closedsystem' when it contracts isometrically and this pro-vides a valuable experimental model for studyingmuscular contraction in man. Force is measuredwith a strain gauge, metabolic heat production ismeasured with a thermal probe (Edwards, McDon-nell and Hill, 1974b) and changes in muscle meta-bolism are followed by chemical analysis of repeatedneedle biopsy samples (Hultman, 1967; Karlsson,1971; Edwards et al., 1972a; Ahlborg et al., 1972).

It is well known that the time an isometric contrac-tion can be sustained depends on the force exerted.From a large number of observations in severalmuscles, Rohmert (1960) defined a curved relationbetween endurance time and force (Fig. 2). Ourresults generally agree with Rohmert's, however,some of our athletes had a greater capacity to sustaincontractions than our sedentary subjects, possiblybecause of superior motivation or because of meta-bolic adaptations in their muscles (Gollnick et al.,1972). The subject's full co-operation is needed inestablishing the correct value for the force of amaximal voluntary contraction (MVC), the standardby which all submaximal force measurements arecompared. In well motivated normal subjects theMVC force is proportional to the body weight (Fig.3). (Body weight was chosen as a standard not onlybecause muscular strength obviously varies with bodysize but because thequadricepsmuscleplaysan impor-tant role in supporting a large part of the body weightineverydaylifeactivities.) In patients there is likely tobe uncertainty as to the validity of MVC measure-ments and whether or not contractions have been

TABLE 1. Energy sources for muscular activity

Short term (anaerobic) sources

1. Adenosine triphosphate (ATP) - adenosine diphosphate (ADP) + inorganic phosphate (Pi) + energy2. Phosphorylcreatine + ADP creatine + ATP3. Glycogen/glucose + Pi + ADP lactate + ATP

Long term (aerobic) sources

1. Glycogen/glucose + ADP +Pi -t02 H20 + CO2 + ATP2. Free fatty acids + ADP + P, + 02 --- H20 + CO2 + ATP


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Muscle fatigue

Refererence(all subjects)

20 40 60 80Force as 0/0 maximum voluntary contraction

FIG. 2. Relationship between force ofcontraction and endurance timefor isometric contractions of the quadriceps muscle, sustained tofatigue. Symbols indicate results in individual subjects studied atHammersmith. The curve, redrawn from Rohmert (1960) is based onmeasurements in thirteen different muscle groups, including the quadri-ceps. Sedentary males, 0 (n = 10); female subjects, * (n = 5); maleathletes, 0 (n = 5); female athletes, A (n = 11).

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FIG. 3. The force of a maximum voluntaiy contraction of the quadri-ceps muscle. Results in children and adults related to body weight(obese subjects excluded). Normal subjects aged 5-38 (n = 53): males,*; females, 0. y = 091x-6 9, r = 0 952, P < 0 001.

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FIG. 4. Thermal probe measurements: rate of rise oftemperature in maximum voluntary contractions com-pared with those in electrically stimulated contractions.Note that muscle can be maximally activated in avoluntary effort. Normal subjects: fresh muscles, 0;fatigued muscles, A. Patients: fresh muscle, 0.

properly sustained to 'fatigue' or stopped prema-turely. The finding of a normal MVC force can bereassuring if the force is consistently low but thequestion is raised whether the patient would not orcould not make a stronger contraction. These possi-bilities can be investigated further by artificiallystimulating the muscle. The extent to which themuscle itself is working normally can then be deter-mined by measuring the metabolic heat productionwith a thermal probe (Edwards et al., 1974b) andcomparing the values obtained with those foundduring maximum voluntary contractions (Fig. 4).For this purpose a fraction (20-40%) of the muscleis stimulated electrically via two skin electrodesplaced proximally and distally on the anterior aspectof the thigh. This technique has been adopted sinceit is less painful than the arguably more reliablemethod of supramaximal stimulation of the femoralnerve. Consistent results have been found and showthat the part of the quadriceps muscle into which thethermal probe is inserted can normally be maximallyactivated by a voluntary effort not only when themuscle is fresh but also when fatigued (Fig. 4). Thepatients with metabolic myopathies studied were alsoable to activate their muscles maximally in a volun-tary effort although in several individuals the abso-lute values obtained in both types of contractionwere lower than normal. Failure to achieve the samerate of temperature rise in a voluntary effort as withelectrical stimulation suggests some disorder in thenervous control of muscular contraction rather than

in the muscle itself. This could be at any level in thenervous system and other evidence is needed to de-cide whether the cause is psychological or the resultof an organic lesion. If the rate of temperature rise issimilar in both types of contraction but low, as whennormal muscle is fatigued, there may be a disorderof neuromuscular transmission, muscle metabolismor excitation-contraction coupling. The last twopossibilities can be distinguished by measuring thecontraction forces elicited with a range of stimula-tion frequencies (Edwards et al., 1974a) and by needlebiopsy studies of muscle metabolism (see below).Failure of neuromuscular transmission can be recog-nized by examination of the force records (ormuscle action potentials) during repetitive nervestimulation (Desmedt, 1973) and by the Edro-phonium test.Thermal probes can now be made in the form of

fine needles or thermocouple wires which can beinserted into almost any muscle. Myothermal tech-niques, though at present at a relatively early stageof development, may in the future provide usefulinformation which is complementary to that obtain-able by current electromyographic techniques.

Objective information about fatigue in sustainedisometric contractions can be obtained by studyingthe changes in muscle chemistry during contraction.This requires chemical analysis of repeated needlebiopsy samples. Accounts of the needle biopsy tech-nique, its history and use in diagnosis and researchhave been published elsewhere (Edwards, 1971;Edwards et al., 1973) and practical details have beenillustrated in a colour film with sound commentary(Edwards, 1973).The immediate energy source for muscular activity

is adenosine triphosphate (ATP) (Table 1). This isresynthesized continuously by breakdown of phos-phorylcreatine, by anaerobic glycolysis and by oxida-tion of blood-borne glucose and free fatty acids.Occlusion of the circulation during an isometriccontraction means that the oxidative energy con-tribution is limited to that resulting from the smallamount of oxygen stored with myoglobin. This con-tribution was eliminated in our experimental studyof anaerobic energy supply mechanisms during mus-cular contraction by inflating a thigh cuff to 200mmHg 3 min before the start of the contraction.Needle biopsies were obtained immediately beforeand at the end of isometric contractions held at aforce of 50 %Y MVC, and sustained to fatigue. Thepatients studied presented at Medical Clinics com-plaining of muscle weakness and fatigue but histo-logical, histochemical and electronmicroscopicalexamination of needle biopsy samples (Edwards etal., 1973) revealed no abnormalities. Muscle contentsof ATP, phosphorylcreatine and lactate were thesame in the patients as in the normal subjects both


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Muscle fatigue 141

at rest and at fatigue (Fig. 5). This provides objectiveevidence that the patients were capable of drivingtheir muscles to the same extent as the normal sub-jects and that energy supply processes were workingnormally. The complaint of 'fatigue' in these patientsdoes not, therefore, appear to be due to abnormalenergy supply during contraction.

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Rest FatigueFIG. 5. Analysis of needle biopsy samples of muscleobtained before and at the end of fatiguing isometriccontractions of the quadriceps muscle in normal subjectsand patients. The patients presented with the complaintsof muscle weakness and/or fatigue but EMG and histo-logical, histochemical and electronmicroscopical studieson needle biopsy samples revealed no abnormalities.Note the similar pattern of changes in both groups indi-cating that the patients had a normal ability to make useof muscle energy supply processes. Normal males (11),hatched; male patients (5), stippled.

The relation between rise in lactate (indicating thecontribution of anaerobic glycolysis) and phospha-gen (ATP + phosphorylcreatine) depletion, hereused as the 'internal' standard of metabolic activity,is shown in Fig. 6. Hyperthyroid patients had valuesin the normal range. As expected, the patient withMcArdle's Disease (McArdle, 1951) which is charac-terized by a lack of myophosphorylase (Mommaertset al., 1959) did not produce lactate despite a fall inphosphagen. The patients with hypothyroid myo-pathy and alcoholic myopathy had reduced musclelactate production during activity. Evidence of im-paired anaerobic glycolysis has already been reportedin some alcoholic patients (Perkoff, Hardy andVelez-Garcia, 1966) but not as such in hypothyroidmuscle disease.The finding of a partial impairment of anaerobic

glycolysis is interesting but to take this matter further

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FlI. 6. Relation between muscle lactate production anddepletion of phosphagen (ATP + phosphorylcreatine)during fatiguing isometric contractions of quadricepsmuscle in patients with metabolic myopathies. Shadedarea represents the results for normal muscle (patientsand normal subjects) given in Fig. 5. Metabolic myo-pathies: hyperthyroid, A; hypothyroid, A; alcoholic,O; McArdle's disease, *.

it is necessary to consider muscle structure and howit is altered in disease. Normal muscle comprisestwo main fibre populations (Fig. 7) when typed ac-cording to myosin ATPase activity (Dubowitz andBrooke, 1973). Type I fibres have a low ATPaseactivity but are rich in myoglobin, mitochondria andoxidative enzymes and are generally slow contract-ing. Type II fibres have a high ATPase activity, ahigh glycolytic activity and are generally fast con-tracting. It appears from recent studies in man thatType I fibres are recruited for long sustained iso-metric contractions at low forces (Gollnick et al.,1974a) and in dynamic exercise of low intensity(Gollnick, Piehl and Saltin, 1974b). Type II fibres arerecruited for higher contraction forces and in dyna-mic exercise of high intensity. An interesting possi-bility raised by these investigations is that depletionof energy stores in one or other of the muscle fibretypes might be responsible for fatigue in the various


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FIG. 7. Needle biopsy of normal vastus lateralis stained for myosin ATPaseactivity ( x 288). Note pale stained (Type I) and dark stained (Type II) fibresare approximately equal in size and frequency.

forms of exercise studied. Morphological studies ofneedle biopsy samples (Edwards et al., 1973) revealedatrophy of the Type II fibres in the patients withhypothyroid and alcoholic myopathies. Whether theType II fibre atrophy, a nonspecific finding in anumber of other conditions, simply reflects disuse,with selective preservation of the Type I fibres witha low recruitment threshold is not known with anycertainty, though this is clearly a possible explana-tion. The observed impairment in anaerobic glyco-lysis in these patients could be due to the reducedvolume of Type II (glycolytic) fibres in muscle butthis may be too simple an explanation since no in-formation is available for the relative glycolytic ratesof the two fibre types in human muscle. A newdevelopment which may be helpful is to study themetabolic characteristics of the individual fibre typesin -needle biopsy samples from patients with meta-bolic myopathies. Glycogen determinations havealready been made in single fibre fragments of nor-mal muscle (Essen and Henriksson, 1974) and pre-liminary studies of our own suggest that thisapproach could also be used for the study of othermetabolic characteristics of individual fibre types indiseased human muscle.There are many unsolved problems associated with

human muscle fatigue. Quantitation of muscle func-tion in simple clinical tests could help in the evalua-tion of therapies, while detailed physiological andmetabolic studies may reveal the extent to which

weakness is due to impaired function of the cellularcontractile machinery of muscle. Needle biopsymakes the study of muscle structure and chemistryfeasible in a wider range of clinical conditions thanhas hitherto been possible with open biopsy. It istoo early to expect solutions to many of the problemspresented by muscle disease but the research toolsdescribed are giving promising results which it ishoped will aid in a more fundamental understandingof myopathies and help in the evaluation of possibletreatments.

AcknowledgmentsResearch described in this paper has been supported by

the Wellcome Trust and the Muscular Dystrophy Group ofGreat Britain.

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DUBOWITZ, V. & BROOKE, M.H. (1973) Muscle Biopsy:A Modern Approach, p. 44. W. B. Saunders: London.

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Muscle fatigue 143

EDWARDS, R.H.T. (1973) Film: percutaneous needle biopsyof skeletal muscle in diagnosis and research. Journal ofPhysiology, 231, 60P.

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EDWARDS, R.H.T., HILL, D.K., JONES, D.A. & MERTON, P.A.(1974a) Fatigue of excitation-contraction coupling afterprolonged stimulation of human muscle. Abstracts ofXXVI International Congress of Physiological Sciences,New Delhi, October, 1974.

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