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.