Muscle cell function during prolonged activity: cellular mechanisms of fatigue

Abstract

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.

Combined myofibrillar and mitochondrial creatine kinase deficiency impairs mouse diaphragm isotonic function

“…W ithout adequate CK buffering of ADP, this would cause a large increase in ADP concentration after even one contraction. Analogous calculations by others suggest th a t, in th e absence of CK buffering, ADP concentrations rise during muscle activation to levels th a t significantly reduce the shortening velocity of skinned fibers in vitro (1,6). Finally, although there is only lim ited evidence to indicate th a t myoplasmic free calcium concentration influences shortening veloc ity (1), we have recently observed th a t CK[-/ -] Dia has distinctly altered calcium release and sequestration characteristics (unpublished observations) during re petitive activation th a t m ay have profound effects on the excitation-contraction profile of this muscle.…”

“…The factors predisposing muscle to fatigue are felt prim arily to resu lt from an im balance betw een energy supply and dem and (25, 35). The accum ulation of energy m etabo lites in all probability also plays an im portant role (1,6,8). A lteration of th e capacity of skeletal muscle to produce or sustain ATP levels is th u s likely to affect muscle fatigue resistance.…”

Mitochondrial Dysfunction in Skeletal Muscle of Amyloid Precursor Protein-overexpressing Mice

“…The current results suggest that oxidation of the RyRs may be partially responsible for the reduced SR Ca 2ϩ release in the MCK-␤APP muscle. An acidic cytoplasm may affect the rate of Ca 2ϩ uptake into SR by reducing the affinity of the SR Ca 2ϩ ATPase (SERCA) pump to Ca 2ϩ (44,45). Although we did not observe any changes in Ca 2ϩ reuptake parameters (not shown), which in part reflect Ca 2ϩ uptake by the SERCA, in the mice at ages chosen for this study, the rate of Ca 2ϩ uptake is significantly slower in the older MCK-␤APP mice (29).…”

Effects of modulation of nitric oxide on rat diaphragm isotonic contractility during hypoxia

“…The reduction in power output during repetitive contraction is the result of reduction in velocity, because force was clamped at 33.3% of P o . During hypoxic conditions, the accumulation of intracellular metabolites, i.e., ADP and lactate, could be accentuated under repetitive isotonic contraction compared with hyperoxic conditions (2). The rise of ADP concentration has been shown to reduce the shortening velocity (2).…”

“…During hypoxic conditions, the accumulation of intracellular metabolites, i.e., ADP and lactate, could be accentuated under repetitive isotonic contraction compared with hyperoxic conditions (2). The rise of ADP concentration has been shown to reduce the shortening velocity (2). Therefore, the sensitivity of muscle fatigue to hypoxia is greater than that to hyperoxia.…”