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]), others reported that small increases in [K] 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 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] 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 and ClC-1 channels are activated. K 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.