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

Abstract

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 (KATP 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 KATP and ClC-1 channels are activated. KATP 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.

A century of exercise physiology: effects of muscle contraction and exercise on skeletal muscle Na+,K+-ATPase, Na+ and K+ ions, and on plasma K+ concentration—historical developments

“…In contrast, an eventual decline in maximal NKA activity by whichever mechanism is responsible may then allow greater increases in interstitial [K + ], that could then have inhibiting effects on muscle function, i.e., fatigue. This dual role of elevated [K + ] in muscle is discussed in our companion review (Renaud et al 2023 ). More intensive focus on muscle NKA activity and exercise is required in humans, including comparison of multiple methodologies to resolve current controversies such as the proposed inactivation of maximal NKA activity with exercise.…”

“…In 1940, Fenn summarised key perspectives about the physiological importance of K + : (i) “…the cells are permeable to K + but not to Na + ”; (ii) “the activity of muscle is always accompanied by a loss of K + ”; (iii) “the loss of K + is in general proportional to the duration and the intensity of the contraction”; (iv) “possibly the progressive loss of K + is one of the factors which causes the intensity of contraction to decrease” and finally, (v) “in small concentrations potassium is excitatory and in larger concentrations it is inhibitory” (Fenn 1940 ). These dual physiological roles of K + , excitatory (now known as potentiating) and depressive (possibly as part of fatigue) are extensively discussed in our companion review (Renaud et al 2023 ).…”

“…The section concludes with a focus on human muscle, including the muscle cation changes with exercise in humans and of NKA. The important physiological roles of NKA in attenuating the K + -induced force depression and optimising muscle contraction at the onset of muscle activity are detailed in our companion review (Renaud et al 2023 ). A timeline of key developments in the measurements of Na + and K + in skeletal muscle at rest and with exercise, the discovery of NKA and the effects of exercise on muscle NKA activity, content, and isoforms are shown in Fig.…”

“…Collectively, these studies demonstrated that in isolated, intact slow twitch and fast twitch muscles in rats, NKA was rapidly and substantially activated in an activation-frequency dependent manner by contractions even as short as 1–10 s, with elevated activity sustained for a considerable period post-contraction. Elevated NKA activity has important implications for muscle function: (i) in the maintenance of membrane excitability during contractions, by counteracting the Na + influx and K + efflux associated with AP’s, which preserves Na + and K + gradients and directly by contributing electrogenically to resting E m (Renaud et al 2023 ); (ii) in the post-exercise restoration of excitability and (iii) in minimising the exercise hyperkalaemia and enabling its subsequent rapid recovery post-exercise, which also accounts for the hypokalaemia that can occur for several minutes after high intensity exercise (Sect. Specific intervention effects on plasma [K + ] with exercise, linked with perturbations in muscle NKA activity ).…”

“…This research culminated in understanding the effects of muscle contraction and exercise on muscle Na + and K + , NKA and on plasma K + concentration, now with applications in medicine via chronic disease, genetic NKA mutations, in muscle, integrative and exercise physiology and in sport and exercise science. This review will not discuss the physiological significance of the changes in Na + , K + and NKA activity in regard to sarcolemmal excitability (defined as a reduction in AP amplitude or a complete loss in the capacity of the sarcolemma to generate an AP compared to AP measured in unfatigued and normal physiological conditions), on force potentiation and depression as well as the mechanisms of fatigue, as this is extensively reviewed in our companion review (Renaud et al 2023 ). Furthermore, details on in-vivo and in-vitro regulation of muscle NKA, K + and plasma [K + ] with exercise are detailed elsewhere (Hostrup et al 2021 ; Lindinger and Cairns 2021 ; Pirkmajer and Chibalin 2016 ).…”