Role of Na + ,K + ‐pumps and transmembrane Na + ,K + ‐distribution in muscle function

Na + ,K + ‐ATPase situated in the plasma membrane mediates active extrusion of Na + and intracellular accumulation of K + . This transport system – the Na + ,K + ‐pump – is the major regulator of the transmembrane distribution of Na + and K + , and is itself subject to regulation by a wide variety of factors in skeletal muscles. The excitation of skeletal muscles is elicited by a rapid influx of Na + , followed by an equivalent efflux of K + across sarcolemmal and t‐tubular membranes. Due to their size and sudden onset, these events constitute the major transport challenge for the Na + ,K + ‐pumps. Skeletal muscles contain the largest single pool of K + in the organism. During intense exercise, the Na + ,K + ‐pumps cannot readily reaccumulate K + into the muscle cells. Therefore, the working muscles undergo a net loss of K + , causing up to a doubling of the K + concentration in the arterial blood plasma in less than 1 min and even larger increases in interstitial K + . This may induce depolarization, loss of excitability and force, in particular in muscles, where the excitation‐induced passive Na + ,K + ‐fluxes are large. During continuous stimulation of isolated rat muscles, there is a highly significant correlation between the rise in extracellular K + and the rate of force decline. Fortunately, excitation increases the Na + ,K + ‐pumping rate within seconds. Thus, maximum activation of up to 20‐fold above the resting transport rate may be reached in 10 s, with utilization of all available Na + ,K + ‐pumps. In muscles, where excitability is reduced by pre‐exposure to high [K + ] o , acute activation of the Na + ,K + ‐pumps by hormones or intermittent electrical stimulation restores excitability and contractility. In working muscles, the Na + ,K + ‐pumps, due to rapid activation of their large transport capacity, play a dynamic regulatory role in the from second to second ongoing restoration and maintenance of excitability and force. Excitation is a self‐limiting process that depends on the leak/pump ratio for Na + and K + . Acute inhibition of the Na + ,K + ‐pumps with ouabain or downregulation of the Na + ,K + ‐pump capacity clearly reduces contractile endurance in isolated muscles. The Na + ,K + ‐pumps are a limiting factor for contractile force and endurance. This is in particular noted if their capacity is reduced because of inactivity or disease. For these reasons, tight regulation of the Na + ,K + ‐pumps is crucial for the maintenance of plasma K + , membrane potential and excitability in skeletal muscle. This is achieved by:1 acute activation of the Na + ,K + ‐pumps elicited by excitation, catecholamines, insulin, insulin‐like growth factor I, calcitonins and amylin; and 2 long‐term regulation of the content of Na + ,K + ‐pumps exerted by thyroid hormones, adrenal steroids, insulin, training, inactivity, fasting, K + ‐deficiency or K + ‐overload.In conclusion, the Na + ,K + ‐pump is a central target for regulation of Na + ,K + ‐distribution, important for the contractile performance of skeletal muscles, the pathophysiology of several diseases and for therapeutic intervention.