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.