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

Abstract

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 α1-subunit protein expression was increased 1.6-fold ( P < 0.05), whereas α2- 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 α1-, α2-, 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 α1-subunit-regulating transcription factor ZEB (AREB6) and α1 mRNA expression were increased after HFD and restored by ET. DNA binding activity of Sp-1, a transcription factor involved in the regulation of α2- 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 α2-subunit to plasma membrane was impaired by HFD, whereas α1-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 α2-subunit, may contribute to impaired ion homeostasis in insulin-resistant states such as obesity and type 2 diabetes.

Changes in cardiac Na+/K+-ATPase expression and activity in female rats fed a high-fat diet

“…Numerous studies show significant gender differences in the relative amount of α1 and α2 catalytic isoforms and the activity of Na + -K + -ATPase [44,24,45,46]. In our study, unaltered Na + /K + -ATPase activity despite the reduced content of its ɑ1 subunit may be explained by the fact that rodent α1-subunit isoform has a very low affinity to ouabain, and ouabain-sensitive methods largely reflect the α2-subunit content [47,48]. Michea et al…”

Effect of exercise and training on phospholemman phosphorylation in human skeletal muscle

“…Swimming exercise training in rats for 5 days increased PLM phosphorylation on Ser 68 (18). Two weeks of intense training in soccer players increased PLM phosphorylation on Ser 68 (50).…”

“…The protein concentration of the resulting supernatant was determined using a commercial kit (Bio-Rad, Richmond, CA). To facilitate detection of the sodium pump ␤ 1-and ␤2-subunits, sugar residues were removed with peptide-N-glycosidase F, as described (18).…”

Hypomagnesemia in Type 2 Diabetes: A Vicious Circle?

“…Additionally, insulin has been shown to increase Na + -K + -ATPase activity in several tissues including heart and muscle (111,112). Na In the complex context of T2DM, many factors may play a role in the development of hypomagnesemia.…”