D. A. Jones

Mechanical influences on long‐lasting human muscle fatigue and delayed‐onset pain.

1. The influence of three mechanical factors, force, muscle length and passive lengthening, on long‐lasting changes in voluntary force generation, the force:frequency relationship and the development of tenderness has been studied in healthy human skeletal muscle. The elbow flexors were used in all studies. The effect of muscle length was also investigated in the quadriceps and adductor pollicis muscles. Eighty maximal voluntary contractions (MVCs) were performed: one contraction, lasting approximately 2 s, every 15 s. The MVC and force:frequency relationships were measured before and immediately after the exercise and, together with an assessment of tenderness, at 24 h intervals thereafter. 2. In a series of experiments designed to investigate the effects of force, eccentric (lengthening) contractions were found to cause greater fatique and delayed‐onset muscle pain than either isometric or concentric (shortening) contractions. There were, however, no substantial differences between the effects of isometric and concentric contractions. Changes in MVC took 24‐48 h to return to normal while the low‐frequency fatigue required 3‐4 days to recover. 3. Passive lengthening with a comparable number of movements over the full range had no effect on the force generation of the muscle, nor did it cause any muscle pain. 4. In the series of experiments designed to investigate the effects of length, isometric MVCs were performed at either short or long length and the muscles subsequently tested at an intermediate length. The contractions at long length resulted in greater low‐frequency fatigue and pain, despite the fact that they generated less force than those at the short length. 5. The results demonstrate that there is no simple relationship between the force generated during exercise and the development of long‐lasting muscle fatigue and pain. Furthermore, there is a length‐dependent component in the generation of low‐frequency fatigue and muscle pain.

Experimental skeletal muscle damage: the nature of the calcium‐activated degenerative processes

Abstract. The role of calcium‐activated degenerative processes in the efflux of enzyme from experimentally damaged mouse muscle has been studied using an isolated mouse soleus muscle preparation. Inhibition of mitochondrial activity with dinitrophenol or sodium cyanide was found to cause a large efflux of enzyme. This was largely prevented by withdrawal of the extracellular calcium suggesting that mitochondrial calcium overload does not play a major role in the damage leading to enzyme efflux.

Changes in force and intracellular metabolites during fatigue of human skeletal muscle.

1. The relationship between intracellular metabolites and the generation of force during fatigue has been examined in the first dorsal interosseous muscle of the hand. With the arm made ischaemic, the muscle was fatigued by three bouts of maximal voluntary contraction, leaving approximately three minutes ischaemic rest between contractions. During one series of experiments intracellular phosphorus metabolites were measured by nuclear magnetic resonance during the intervals between the fatiguing contractions: in the second series contractile properties were tested with brief electrical stimulation during the rest intervals. 2. The relationships between loss of force and change in metabolite concentrations obtained with four normal subjects were compared with those from one subject with myophosphorylase deficiency (MPD) who could not utilize muscle glycogen and therefore produced no hydrogen ion from glycolysis during exercise. 3. For both the MPD and normal subjects the relationship between relative force loss and inorganic phosphate (Pi) concentration was curvilinear, force changing little in the early stages of the contraction when the intracellular Pi was accumulating rapidly but falling faster when the Pi was above 25 mM and increasing relatively slowly. 4. In the normal subjects intracellular pH fell from a mean of 7.03 +/‐ 0.01 (mean +/‐ S.E. of mean, n = 19) in the fresh muscle to 6.51 +/‐ 0.02 at the end of the fatiguing exercise; force, as a percentage of the initial value, fell in proportion to the increase in H+ concentration. In the MPD subject pH did not change and force loss was therefore independent of H+ accumulation. In the normal subjects the force of the fatiguing muscle showed an approximately linear relationship with the concentration of the monobasic form of inorganic phosphate. However, the MPD subject showed a quite different relationship, with force loss being much greater for a given concentration of monobasic phosphate. This result indicates that monobasic phosphate is not a unique determinant of force loss in fatigued muscle. 5. During the first 60 s of recovery in the normal subjects, pH remained low while force recovered, indicating a mechanism of force loss that was independent of H+ accumulation. However, the recovery of force was not complete, so that for comparable phosphocreatine contents the recovering, more acid, muscle generated less force than the muscle that was being fatigued. It was estimated that H(+)‐dependent and independent mechanisms contributed roughly equally to the observed force loss. The relationship between force and the concentration of monobasic phosphate differed in fatiguing and recovering muscle.

Zinc homeostasis in man: studies using a new stable isotope-dilution technique

A new method has been developed for the study of zinc metabolism in man using the stable isotope 67Zn. The technique involves intravenous infusion of the isotope followed by measurements of the plasma and faecal enrichments over a period of days. A procedure for the analysis of Zn isotopes in plasma and faeces is described which requires the separation of Zn from other elements using the chelator dithizone before analysis by thermal-ionization mass spectrometry. The stable isotope technique has been used in conjunction with a metabolic balance study to obtain measurements of Zn absorption and gastrointestinal secretion in a normal subject. Preliminary measurements of the size of the exchangeable pool of Zn have been made as have estimates of the rates of plasma and whole-body Zn turnover. Following an increase in dietary Zn the body appeared to respond in two ways. The gastrointestinal secretion of Zn increased immediately, but only by a relatively small amount. The absorption of Zn initially increased in proportion to the increase in dietary levels but then decreased within 4 d by an amount sufficient to restore Zn balance.

Fibre areas and histochemical fibre types in the quadriceps muscle of paraplegic subjects

With the advent of functional electrical stimulation (FES) there is the possibility of paraplegic patients regaining some degree of locomotor activity. It is of interest to document the changes in composition histochemistry and size of muscle fibres in such patients both before and after such therapy. We have examined biopsy specimens from quadriceps muscles obtained from 7 male patients, age range 24-47 years, who had been paraplegic for times ranging from 11 months to 9 years and we report the histochemical appearance of the muscle the fibre type composition and the mean fibre areas. In 5 of the 7 subjects there was a marked or complete predominance of fibres which stained as type 2 with the ATPase reaction at pH 9.4. At acid pH these fibres were seen to be predominantly 2B (fast fatigable). The 2 subjects who had been paralysed for the shortest periods had proportions of type 1 fibres which were relatively well preserved. The mean fibre areas of type 2 fibres were below the normal range (2500-7500 microns 2) in every case as were the type 1 fibres in the 4 patients in which these were still present. There was no relationship between the length of time the patient had been paralysed and the mean fibre areas which suggests that atrophy occurs fairly quickly following loss of voluntary control and precedes the loss of type 1 characteristics. Our findings provide an explanation for the rapid onset of fatigue in paraplegic patients taking part in FES programmes since muscles deficient in type 1 fibres will be unable to maintain force for any length of time.

CELLULAR INFILTRATES IN HUMAN SKELETAL-MUSCLE - EXERCISE INDUCED DAMAGE AS A MODEL FOR INFLAMMATORY MUSCLE DISEASE

The type and distribution of mononuclear cell infiltrates in muscle biopsies taken from 9 subjects at differing times after exercise in which the muscle is stretched (eccentric exercise) has been characterised. The appearances are compared to those seen in muscle from patients with inflammatory muscle disease. After exercise infiltrating cells were seen in perivascular, perimysial and endomysial regions, the extent being greater in the later biopsies (9-14 days). The predominant cell type was the macrophage (46-100% of all infiltrating cells), the remainder were T lymphocytes with a predominance of the CD4 positive helper/inducer subset. Approximately one third of the T cells expressed DA2 (class 2) antigen indicating that they were activated. Very few B lymphocytes and no Leu7 positive cells were seen. There was evidence of class 1 expression on some of the damaged muscle fibres. The appearance of the experimentally damaged muscle in normal subjects was very similar to untreated polymyositis suggesting that a proportion of the infiltrating cells seen in this disease may be present as part of a natural response to damage rather than being its cause.

Size and composition of the calf and quadriceps muscles in Duchenne muscular dystrophy

Calf and quadriceps muscle size and composition have been examined in 5 control subjects and 12 boys (aged 7-18 years) with Duchenne muscular dystrophy using computed tomography (CT) and quantitative histochemistry of needle biopsy samples of muscle. In assessing the size of leg muscles it was found that in control subjects the muscle cross-sectional area was related to the cross-sectional area of the femur. The calf muscles in the patients were enlarged both relative to the quadriceps and absolutely when related to the cross-sectional area of the femur used as an index of stature. The enlargement of the calf was the result of accumulations of fat and connective tissue in the presence of relatively normal (compared to femur size) amounts of muscle tissue. Although hypertrophied muscle fibres were a feature of the biopsy samples in the calf the extent of this was insufficient to contribute appreciably to the total muscle enlargement.

Loss of power during fatigue of human leg muscles.

1. We have investigated the loss of power seen during high‐intensity exercise of human leg muscles such as might occur during sprinting. Subjects exercised the quadriceps and hamstring muscle groups using a Cybex dynamometer at an angular velocity of 90 deg s‐1 once a second for 6 min. At 1 min intervals the quadriceps were electrically stimulated via the femoral nerve to produce an isometric contraction which was then released into an isokinetic shortening contraction at 90 deg s‐1. 2. The extent of central fatigue was assessed by comparing the force of a voluntary isokinetic contraction with that elicited by electrical stimulation during isokinetic releases. Two subjects were repeatedly tested. In the first series of experiments, exercising the quadriceps of one leg, the instantaneous power fell to about 50% over the course of 2 min and remained constant for the rest of the exercise. For one subject the voluntary and electrically stimulated forces declined in parallel while for the second subject the voluntary force was 10% less than the stimulated force at the end of the exercise. These results show that central fatigue represented a minor factor contributing no more than one‐fifth of the total loss of power in these circumstances. 3. In a second series of experiments the subjects alternately contracted the quadriceps and the hamstrings of both legs in an exercise which had a high rating of perceived exertion and entailed considerable respiratory and cardiovascular effort. The time course and proportionate loss of power were very similar to those seen with the one‐leg exercise and neither subject showed evidence of significant central fatigue. The pattern of force loss was very similar for the hamstrings. We conclude that, for determined subjects, afferent feedback from muscles, tendons and joints or from the respiratory and cardiovascular systems does not have a major role in inhibiting voluntary activation of the quadriceps during heavy exercise. 4. In both series of experiments the power output during electrically stimulated isokinetic contractions was reduced to 50% of the initial value after 2 min of exercise while the isometric force, measured immediately before the release, fell to only 75%. This suggests that fatigue affects isometric and shortening contractions to different extents and the loss of power may be due to a combination of factors, only one of which is evident in the loss of isometric force.

The metabolic causes of slow relaxation in fatigued human skeletal muscle.

1. The relationship between slowing of relaxation and changes of intracellular pH and phosphorous metabolites has been examined in human skeletal muscle during the development of fatigue and subsequent recovery. Results obtained with normal subjects have been compared with those from a subject with myophosphorylase deficiency (MPD) who produced no H+ from glycolysis during exercise and therefore afforded the opportunity of assessing the role of H+ in the slowing of relaxation. 2. Subjects fatigued the first dorsal interosseous muscle in a stepwise fashion under ischaemic conditions, with intervals between the fatiguing contractions during which the relaxation rate was measured from brief tetanic contractions and the muscle phosphorous metabolites and pH were measured by nuclear magnetic resonance spectroscopy. 3. After 21 s maximal voluntary contraction under ischaemic conditions, relaxation in the MPD subject slowed to approximately 50% of the rate in the fresh muscle at a time when the intramuscular pH had not changed. This demonstrates that there is a mechanism causing slowing of relaxation that is independent of H+ accumulation. 4. The normal subjects showed a slow recovery of relaxation compared to the MPD subject when the circulation was restored. The main difference in the intracellular metabolite concentrations between MPD and normal subjects at this time was that, for the latter, the pH remained low (around 6.5) for at least 60 s after the circulation was restored. The results suggest that the slow recovery is a consequence of continuing acidosis, i.e. the existence of a pH‐dependent mechanism of slowing. 5. The existence of a pH‐dependent mechanism was further indicated by the fact that for the normal subjects, for a similar intracellular concentration of phosphocreatine, relaxation of the recovering muscle was approximately half that of the fatiguing muscle. This was at a time when the pH of the recovering muscle was 0.3‐0.4 units less than in the partially fatigued muscle. 6. The results show that in normal muscle there are at least two processes that lead to slow relaxation in fatigued muscle: one due to H+ accumulation, the other being independent of H+.

Zinc absorption in the rat.

1. A method of studying zinc absorption in rats has been developed in which binding of radioactive Zn to the intestinal mucosa and absorption into the carcass was determined at different times after administration by stomach tube. 2. This technique has been used to evaluate different hypotheses concerning the control of Zn absorption and to examine the processes by which this occurs. 3. The proportion of radioactive Zn absorbed into the carcass was found to be dependent on the Zn status of the animals but that found within the small intestinal wall was independent of this, indicating the existence of two mechanisms of Zn absorption. 4. One of these two mechanisms has been shown to be induced by a low dietary Zn content while the other was shown to be insensitive to this. This latter mechanism predominated in rats of normal dietary Zn, status and a study of the characteristics of this process indicated that the quantity of Zn absorbed was proportional to the dietary Zn content over the normal range of intake. This implies that normally Zn homeostasis in rats is achieved through variations in Zn excretion. The additional mechanism of Zn absorption only becomes fully active at levels of dietary Zn below 0.24 MUMOL/g diet.