Na,K-ATPase regulation in skeletal muscle

Abstract

Skeletal muscle contains one of the largest and the most dynamic pools of Na,K-ATPase (NKA) in the body. Under resting conditions, NKA in skeletal muscle operates at only a fraction of maximal pumping capacity, but it can be markedly activated when demands for ion transport increase, such as during exercise or following food intake. Given the size, capacity, and dynamic range of the NKA pool in skeletal muscle, its tight regulation is essential to maintain whole body homeostasis as well as muscle function. To reconcile functional needs of systemic homeostasis with those of skeletal muscle, NKA is regulated in a coordinated manner by extrinsic stimuli, such as hormones and nerve-derived factors, as well as by local stimuli arising in skeletal muscle fibers, such as contractions and muscle energy status. These stimuli regulate NKA acutely by controlling its enzymatic activity and/or its distribution between the plasma membrane and the intracellular storage compartment. They also regulate NKA chronically by controlling NKA gene expression, thus determining total NKA content in skeletal muscle and its maximal pumping capacity. This review focuses on molecular mechanisms that underlie regulation of NKA in skeletal muscle by major extrinsic and local stimuli. Special emphasis is given to stimuli and mechanisms linking regulation of NKA and energy metabolism in skeletal muscle, such as insulin and the energy-sensing AMP-activated protein kinase. Finally, the recently uncovered roles for glutathionylation, nitric oxide, and extracellular K(+) in the regulation of NKA in skeletal muscle are highlighted.

Inhibition of glycogenolysis prolongs action potential repriming period and impairs muscle function in rat skeletal muscle

“…The finding here of a similar increase in the repriming period with GP inhibition or glycogen removal in combination with partial t‐system depolarization clearly demonstrates the importance of glycogenolytically derived ATP for Na + ,K + ‐ATPase activity. In depolarized muscle fibres, Na + ,K + ‐ATPase energy demand is expected to be high (Clausen, ; Pirkmajer & Chibalin, ), further stressing the importance of readily available ATP production for the Na + ,K + ‐ATPases. In support of this, Dutka and Lamb () found that stimulation of glycolytic ATP production by the addition of phosphoenolpyruvate decreases the repriming period in partly depolarized, but not well‐polarized, fibres (Dutka & Lamb, ).…”

A skeletal muscle L-type Ca2+ channel with a mutation in the selectivity filter (CaV1.1 E1014K) conducts K+

“…During the repolarization phase of the skeletal muscle action potential, K + exits the myoplasm via delayed rectifier K + channels to restricted extracellular compartments before being returned actively to the fiber by the Na + /K + -ATPase (31) or passively via inward rectifier K + channels when the membrane potential becomes more negative than E K (32)(33)(34)(35). During LFS, these clearance mechanisms are sufficient to maintain the K + gradient (31). However, transport by the pump and inward rectifier channels cannot keep pace with the K + efflux via delayed rectifier channels during prolonged depolarization or HFS protocols similar to those employed by Lee and colleagues (15,30,[33][34][35][36][37][38][39].…”

Early vertebrate origin and diversification of small transmembrane regulators of cellular ion transport

“…, ; Tang et al . ; Pirkmajer & Chibalin, ). Expression of tetrapod FXYD4 is regulated by aldosterone (Capurro et al .…”

“…FXYDs in fishes and mammals are regulated by hormones (Despa et al 2005;Tipsmark et al 2010Tipsmark et al , 2011Tang et al 2012;Pirkmajer & Chibalin, 2016). Expression of tetrapod FXYD4 is regulated by aldosterone (Capurro et al 1997;Brennan & Fuller, 1999;Shi et al 2001), a major mineralocorticoid in terrestrial vertebrates (Rossier et al 2015).…”