Role of Na+,K+-pumps and transmembrane Na+,K+-distribution in muscle function. The FEPS lecture - Bratislava 2007.

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.