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.