Exercise and fatigue: integrating the role of K(+), Na(+) and Cl(−) in the regulation of sarcolemmal excitability of skeletal muscle

Perturbations in K(+) have long been considered a key factor in skeletal muscle fatigue. However, the exercise-induced changes in K(+) intra-to-extracellular gradient is by itself insufficiently large to be a major cause for the force decrease during fatigue unless combined to other ion gradient changes such as for Na(+). Whilst several studies described K(+)-induced force depression at high extracellular [K(+)] ([K(+)](e)), others reported that small increases in [K(+)](e) induced potentiation during submaximal activation frequencies, a finding that has mostly been ignored. There is evidence for decreased Cl(−) ClC-1 channel activity at muscle activity onset, which may limit K(+)-induced force depression, and large increases in ClC-1 channel activity during metabolic stress that may enhance K(+) induced force depression. The ATP-sensitive K(+) channel (K(ATP) channel) is also activated during metabolic stress to lower sarcolemmal excitability. Taking into account all these findings, we propose a revised concept in which K(+) has two physiological roles: (1) K(+)-induced potentiation and (2) K(+)-induced force depression. During low-moderate intensity muscle contractions, the K(+)-induced force depression associated with increased [K(+)](e) is prevented by concomitant decreased ClC-1 channel activity, allowing K(+)-induced potentiation of sub-maximal tetanic contractions to dominate, thereby optimizing muscle performance. When ATP demand exceeds supply, creating metabolic stress, both K(ATP) and ClC-1 channels are activated. K(ATP) channels contribute to force reductions by lowering sarcolemmal generation of action potentials, whilst ClC-1 channel enhances the force-depressing effects of K(+), thereby triggering fatigue. The ultimate function of these changes is to preserve the remaining ATP to prevent damaging ATP depletion.