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Am J Physiol Endocrinol Metab 297: E38-E49, 2009. First published April 14, 2009; doi:10.1152/ajpendo.90990.2008
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Altered expression and insulin-induced trafficking of Na+-K+-ATPase in rat skeletal muscle: effects of high-fat diet and exercise

Dana Galuska,1 Olga Kotova,2 Romain Barrès,2 Daria Chibalina,2 Boubacar Benziane,2 and Alexander V. Chibalin2

Departments of 1Physiology and Pharmacology and 2Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

Submitted 11 December 2008 ; accepted in final form 14 April 2009

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 β1-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 β1-subunit expression and Na+-K+-ATPase activity to control levels and reduced β2-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 β1-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.

phospholemman; protein expression; transcription factors; sodium pump


Address for reprint requests and other correspondence: A. V. Chibalin, Dept. of Molecular Medicine and Surgery, Integrative Physiology, Karolinska Institutet, von Eulers väg 4a, 4 tr, SE-171 77, Stockholm, Sweden (E-mail: Alexander.Chibalin{at}ki.se)






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