The 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⁺ (1) and is itself subject to regulation by a wide variety of factors in skeletal muscles (2).

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 the 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 one min and even larger increases in the interstitial K⁺. This may induce depolarisation, loss of excitability and force, in particular in muscles, where the excitation-induced passive Na⁺,K⁺-fluxes are large. Thus, excitation is a self-limiting process, that depends on the leak/pump ratio for Na⁺ and K⁺. Fortunaly, 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 (2). In muscles, where excitability is reduced by preexposure to high [K⁺]_o, low [Na⁺]_o, depolarizing agents or even mechanical damage, acute activation of the Na⁺,K⁺-pumps by hormones 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. The Na⁺,K⁺-pumps are a limiting factor for contractile force and endurance. This is in particular noted if their capacity is reduced due to 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 in two ways:

1) By acute activation of the Na⁺,K⁺-pumps elicited by excitation, catecholamines, insulin, IGF-I, calcitonins and amylin.

2) By 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.

The Na⁺,K⁺-pump is a central target for regulation of Na⁺,K⁺-distribution, important for the pathophysiology of several diseases and for therapeutic intervention (3).

References: 

1) JC Skou. Enzymatic basis for active transport of Na⁺ and K⁺ across cell membrane. Physiol Rev, 45: 596-617, 1965.

2) T Clausen. Na⁺-K⁺ pump regulation and skeletal muscle contractility. Physiol Rev 83: 1269-1324, 2003.

3) T Clausen. Clinical and therapeutic significance of the Na⁺,K⁺ pump. Clin Sci 95: 3-17, 1998.