Muscle performance declines during prolonged and intense activity; important components are a reduction in force production and shortening velocity and a prolongation of relaxation. In this review we consider how the changes in metabolites (particularly H+, inorganic phosphate (Pi), ATP and ADP) and changes in sarcoplasmic reticulum Ca2+ release lead to the observed changes in force, shortening velocity and relaxation. The reduced force is caused by a combination of reduced maximum force‐generating capacity, reduced myofibrillar Ca2+ sensitivity and reduced Ca2+ release. The reduced maximum force and Ca2+ sensitivity are largely explained by the effects of H+ and Pi that have been observed in skinned fibres. At least three different forms of reduced Ca2+ release can be recognized but the mechanisms involved are incompletely understood. The reduced shortening velocity can be partly explained by the effects of H+ that have been observed in skinned fibres. In addition it is proposed that ADP, which depresses shortening velocity, increases during contractions to a level that is considerably higher than existing measurements suggest. Changes in Ca2+ release are probably unimportant for the reduced shortening velocity. The prolongation of relaxation can arise both from slowing of the rate of decline of myoplasmic calcium concentration and from slowing of cross‐bridge detachment rates. A method of analysis which separates these components is described. The increase in H+ and the other metabolite changes during fatigue can independently affect both components. Finally we show that reduced force, shortening velocity and slowed relaxation all contribute to the decline in muscle performance during a working cycle in which the muscle first shortens actively and then is stretched passively by an antagonist muscle.

1. The purpose of this study was to examine the effects of reduced glycogen concentration on force, CPa2 release and myofibrillar protein function during fatigue in skeletal muscle. Force and intracellular free Ca2+ concentration ([Ca2P] and 55 + 6 % of initial levels, respectively. These changes were associated with a recovery of muscle glycogen (to 85 + 10 %).5. During fatigue, Ca2+ sensitivity and maximum Ca2P-activated force (Fmax) were depressed but these alterations were fully reversed when muscle glycogen recovered. When glycogen did not recover, Ca2P sensitivity remained depressed but Fmax partially recovered. The altered myofibrillar protein function is probably due to alterations in inorganic phosphate levels or other metabolites associated with reduced levels of muscle glycogen. 6. These data indicate that the reductions in force, Ca2+ release and contractile protein inhibition observed during fatigue are closely associated with reduced muscle glycogen concentration. These findings also suggest that the changes in Ca2P release associated with fatigue and recovery have two components -one which is glycogen dependent and another which is independent of glycogen but depends on previous activity.During repeated tetanic contractions of skeletal muscle balance between rates of ATP utilization (intensity and there is a reduction in force output. This decline in function, duration of contractile activity) and rates of ATP supply referred to as muscle fatigue, has a complex aetiology which (metabolic pathway, substrate supply and muscle fibre type). can involve various metabolic and ionic factors (see Fitts, During repeated contractions at high intensities (i.e. 100%1994; Allen, Liinnergren & Westerblad, 1995) for recent maximum force for -3 min), ATP is resynthesized predominreviews). Metabolic impairment plays a major role in muscle antly by PCr degradation and anaerobic glycolysis (Spriet, fatigue with the extent of impairment dependent on the 1992). Under these conditions there is an accumulation of

1. Measurements have been made of tension development in papillary muscles isolated from the right ventricles of young cats. In some cases membrane potentials have also been recorded, using micro electrodes. 2. Regular contractions at a stimulation rate of 20 min(-1) (the 'standard' rate used in this study) had the following characteristics (30 degrees C): peak tension developed, about 43mN mm(-2); time to peak tension and time to 80% repolarization of the cell membrane, about 400 ms. 3. The corresponding figures for the first contraction after a rest of several minutes (rested state contraction) were: tension developed, about 4mN mm(-2); time to peak tension and time to 80% repolarization of the cell membrane, about 560 ms. Sometimes there was also an early peak in the mechanical response, about 250 ms after stimulation. 4. The time course with which tension development declined when the muscle was allowed to rest was examined under various conditions. It was found to decline more slowly when the muscle was potentiated by raising the bathing Ca2+ concentration and by stimulation at rates above 20 min(-1). 5. Tension development in rested state contractions was found to depend on the Ca2+ and Na+ concentrations in the bathing solution. The full effect of a change in either could be produced by exposing the resting muscle to the altered ionic conditions. 6. These experimental findings have been interpreted in terms of a simple model of the calcium movements involved in excitation-contraction coupling in the myocardial cell.

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SUMMARYIn this study the effects of ATP-sensitive K+ channel modulators were studied in intact single fibres dissected from mouse skeletal muscle. Indo-1 was used to measure [Ca2+]