Altered expression and insulin-induced trafficking of Na+-K+-ATPase in rat skeletal muscle: effects of high-fat diet and exercise

Galuska D, Kotova O, Barres R, Chibalina D, Benziane B, Chibalin AV. Altered expression and insulin-induced trafficking of Na+-K+-ATPase in rat skeletal muscle: effects of high-fat diet and exercise. Am J Physiol Endocrinol Metab 297: E38-E49, 2009. First published April 14, 2009; doi: 10.1152/ajpendo.90990.2008.-Skeletal muscle Na+-K+-ATPase plays a central role in the clearance of K+ from the extracellular fluid, therefore maintaining blood [K+]. Na+-K+-ATPase activity in peripheral tissue is impaired in insulin resistant states. We determined effects of high-fat diet (HFD) and exercise training (ET) on skeletal muscle Na+-K+-ATPase subunit expression and insulin-stimulated translocation. Skeletal muscle expression of Na+-K+-ATPase isoforms and transcription factor DNA binding was determined before or after 5 days of swim training in Wistar rats fed chow or HFD for 4 or 12 wk. Skeletal muscle insulin resistance was observed after 12 wk of HFD. Na+-K+-ATPase alpha(1)-subunit protein expression was increased 1.6-fold (P < 0.05), whereas alpha(2)- and beta(1)-subunits and protein expression were decreased twofold (P < 0.01) in parallel with decrease in plasma membrane Na+-K+-ATPase activity after 4 wk of HFD. Exercise training restored alpha(1)-, alpha(2)-, and beta(1)-subunit expression and Na+-K+-ATPase activity to control levels and reduced beta(2)-subunit expression 2.2-fold (P < 0.05). DNA binding activity of the alpha(1)-subunit-regulating transcription factor ZEB (AREB6) and alpha(1) mRNA expression were increased after HFD and restored by ET. DNA binding activity of Sp-1, a transcription factor involved in the regulation of alpha(2)- and beta(1)-subunit expression, was decreased after HFD. ET increased phosphorylation of the Na+-K+-ATPase regulatory protein phospholemman. Phospholemman mRNA and protein expression were increased after HFD and restored to control levels after ET. Insulin-stimulated translocation of the alpha(2)- subunit to plasma membrane was impaired by HFD, whereas alpha(1)-subunit translocation remained unchanged. Alterations in sodium pump function precede the development of skeletal muscle insulin resistance. Disturbances in skeletal muscle Na+-K+-ATPase regulation, particularly the alpha(2)-subunit, may contribute to impaired ion homeostasis in insulin-resistant states such as obesity and type 2 diabetes.