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. [ABSTRACT FROM AUTHOR]