Repeated, intense use of muscles leads to a decline in performance known as muscle fatigue. Many muscle properties change during fatigue including the action potential, extracellular and intracellular ions, and many intracellular metabolites. A range of mechanisms have been identified that contribute to the decline of performance. The traditional explanation, accumulation of intracellular lactate and hydrogen ions causing impaired function of the contractile proteins, is probably of limited importance in mammals. Alternative explanations that will be considered are the effects of ionic changes on the action potential, failure of SR Ca2+ release by various mechanisms, and the effects of reactive oxygen species. Many different activities lead to fatigue, and an important challenge is to identify the various mechanisms that contribute under different circumstances. Most of the mechanistic studies of fatigue are on isolated animal tissues, and another major challenge is to use the knowledge generated in these studies to identify the mechanisms of fatigue in intact animals and particularly in human diseases.

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Skeletal Muscle Fatigue: Cellular Mechanisms

The muscle glycogen content of the quadriceps femoris muscle was determined in 9 healthy subjects with the aid of the needle biopsy technique. The glycogen content could be varied in the individual subjects by instituting different diets after exhaustion of the glycogen store by hard exercise. Thus, the glycogen content after a fat ± protein (P) and a carbohydrate-rich (C) diet varied maximally from 0.6 g/100g muscle to 4.7 g. In all subjects, the glycogen content after the C diet was higher than the normal range for muscle glycogen, determined after the mixed (M) diet. After each diet period, the subjects worked on a bicycle ergometer at a work load corresponding to 75 per cent of their maximal O2 uptake, to complete exhaustion. The average work time was 59, 126 and 189 min after diets P, M and C, and a good correlation was noted between work time and the initial muscle glycogen content. The total carbohydrate utilization during the work periods (54–798 g) was well correlated to the decrease in glycogen content. It is therefore concluded that the glycogen content of the working muscle is a determinant for the capacity to perform long-term heavy exercise. Moreover, it has been shown that the glycogen content and, consequently, the long-term work capacity can be appreciably varied by instituting different diets after glycogen depletion.

Diet, Muscle Glycogen and Physical Performance

1. The present study was undertaken to test whether creatine given as a supplement to normal subjects was absorbed, and if continued resulted in an increase in the total creatine pool in muscle. An additional effect of exercise upon uptake into muscle was also investigated. 2. Low doses (1g of creatine monohydrate or less in water) produced only a modest rise in the plasma creatine concentration, whereas 5g resulted in a mean peak after 1h of 795 (SD 104) mumol/l in three subjects weighing 76-87 kg. Repeated dosing with 5g every 2h sustained the plasma concentration at around 1000 mumol/l. A single 5g dose corresponds to the creatine content of 1.1 kg of fresh, uncooked steak. 3. Supplementation with 5g of creatine monohydrate, four or six times a day for 2 or more days resulted in a significant increase in the total creatine content of the quadriceps femoris muscle measured in 17 subjects. This was greatest in subjects with a low initial total creatine content and the effect was to raise the content in these subjects closer to the upper limit of the normal range. In some the increase was as much as 50%. 4. Uptake into muscle was greatest during the first 2 days of supplementation accounting for 32% of the dose administered in three subjects receiving 6 x 5g of creatine monohydrate/day. In these subjects renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days. Approximately 20% or more of the creatine taken up was measured as phosphocreatine. No changes were apparent in the muscle ATP content.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation

Methods are described for the determination of glycogen, glycolytic intermediates, and high-energy phosphates in muscle biopsy samples. Initial freezedrying of samples and extraction of metabolites with relatively weak acid are preferred. Normal values in muscle are similar to those found by other workers. Variation in muscle content of ATP, ATP + ADP + AMP, phosphorylcreatine (PC), creatine (Cr), PC + Cr, and glycogen, between legs, between sites on the same muscle, or as a result of error introduced during analysis, was small compared with the between-individuals variance. The importance of the different sources of variance on taking a biopsy is discussed.

Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values.

(1975). Percutaneous Needle Biopsy of Skeletal Muscle in Physiological and Clinical Research. Scandinavian Journal of Clinical and Laboratory Investigation: Vol. 35, No. 7, pp. 609-616.

Percutaneous Needle Biopsy of Skeletal Muscle in Physiological and Clinical Research

Nine volunteers have been examined during prolonged physical exercise to exhaustion at a load of about 60 per cent of W170. Ordinary circulatory parameters were measured as well as the quantities of glycogen, water and electrolytes in muscle tissue obtained by needle biopsy. In a separate study 6 subjects were examined for respiratory quotient under similar exercising conditions. The muscle glycogen fell considerably from a mean of 6.9 per 100g glycogen and fat-free solids to a mean of 1.7 g at the end of exercise. The quantity of muscle glycogen used was correlated both to total energy developed during exercise and also to duration of exercise.

The electrolyte and water content in muscle tissue showed only small changes. Some increase was found in muscle sodium and chloride, and also in the chloride space. The potassium content fell significantly by about 4 per cent of the basal value. None of the circulatory parameters measured showed changes of such magnitude as to have a limiting effect on performance. Two subjects were examined also with glucose infusion during the exercise. The reduction of glycogen, as also the performance of these two subjects, was of the same order of magnitude with and without infusion of glucose. The results suggest that the capacity for prolonged work is directly correlated to the glycogen store in the working muscles.

Muscle Glycogen and Muscle Electrolytes during Prolonged Physical Exercise1

Occlusion of the circulation to the quadriceps muscle for 20 min resulted in decreases in the muscle ATP and phosphorylcreatine (PC) contents of 1 and 32 per cent, respectively, and increases in ADP and AMP of 7 and 37 per cent. Decrease in PC was statistically significant after 4 min of occlusion, suggesting that the local intramuscular oxygen store was sufficiently depleted at this time as to be limiting to normal mitochondrial function. Pyruvate and lactate concentrations in muscle and the lactate to pyruvate ratio were significantly increased after 15 min of occlusion but not before. The calculated local oxygen store in the muscle was 2.0 mmol O2 - (kg dry muscle)-1. Local oxygen store depletion after 4 and 10 min of occlusion was estimated to be 40-50 and 90-100 per cent complete. Increasing time of pre-exercise occlusion resulted in decreased isometric endurance capacity. The observed decreases in endurance, however, were far greater than could be accounted for by any parallel decrease in the local muscle energy stores.

Clinical Physiology: The Effect of Circulatory Occlusion on Isometric Exercise Capacity and Energy Metabolism of the Quadriceps Muscle in Man

The understanding of muscle metabolism and its regulation in situ has been greatly advanced in recent years by the analysis of the levels of metabolic intermediates under differing conditions. Only recently has it been possible to perform similar studies in mail. In the present studies muscle samples have been obtained using the needle biopsy technique (1, 10, 11) and the levels of a number of metabolites in these have been determined by enzymatic micro-methods.

Energy Rich Phosphagens in Dynamic and Static Work

In two healthy male subjects we have made some preliminary observations of the factors influencing endurance and fatigue during successive sustained contractions at two thirds the intensity of a maximal voluntary contraction of the Quadriceps Muscle. In all experiments subjects sat in an adjustable chair (5), measurements being made with a strain gauge attached to the ankle when the knee joint was flexed to 90°. Fig. 1 shows the relationship between the duration of successive contractions and the interval between contractions, both under normal conditions and when the circulation to the leg was occluded using a sphygmomanometer cuff inflated to 250 mm Hg, immediately prior to starting the series. Each subject was allowed at least 24 hours recovery between each experiment. In the absence of circulatory occlusion more than seven holds were possible, the duration of successive holds being significantly related (p =0.016) to the recovery interval. With circulatory occlusion no more than three holds could be sustained, the duration of the second and third holds being unrelated to the recovery interval. As observed by othere (3, 4) the duration of the first hold was not significantly reduced by prior circulatory occlusion suggesting that muscle blood flow was practically arrested at this relative load.

E. Hultman

Papers

Glycogen, glycolytic intermediates and high-energy phosphates determined in biopsy samples of musculus quadriceps femoris of man at rest. Methods and variance of values.

Muscle Glycogen and Muscle Electrolytes during Prolonged Physical Exercise1

Clinical Physiology: The Effect of Circulatory Occlusion on Isometric Exercise Capacity and Energy Metabolism of the Quadriceps Muscle in Man

Energy Rich Phosphagens in Dynamic and Static Work

Isometric Exercise - Factors Influencing Endurance and Fatigue