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Oxidative stress stimulates skeletal muscle glucose uptake through a phosphatidylinositol 3-kinase-dependent pathway

¹Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga; ²Department of Health and Sports Science, Nippon Medical School, Kanagawa, Japan; ³Research Division, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ⁴Faculty of Education and Human Sciences, University of Yamanashi, Yamanashi; and ⁵Liberal Arts Division, Kisarazu National College of Technology, Chiba, Japan

Submitted 8 March 2007 ; accepted in final form 21 February 2008

We determined the acute effects of oxidative stress on glucose uptake and intracellular signaling in skeletal muscle by incubating muscles with reactive oxygen species (ROS). Xanthine oxidase (XO) is a superoxide-generating enzyme that increases ROS. Exposure of isolated rat extensor digitorum longus (EDL) muscles to Hx/XO (Hx/XO) for 20 min resulted in a dose-dependent increase in glucose uptake. To determine whether the mechanism leading to Hx/XO-stimulated glucose uptake is associated with the production of H₂O₂, EDL muscles from rats were preincubated with the H₂O₂ scavenger catalase or the superoxide scavenger superoxide dismutase (SOD) prior to incubation with Hx/XO. Catalase treatment, but not SOD, completely inhibited the increase in Hx/XO-stimulated 2-deoxyglucose (2-DG) uptake, suggesting that H₂O₂ is an intermediary leading to Hx/XO-stimulated glucose uptake with incubation. Direct H₂O₂ also resulted in a dose-dependent increase in 2-DG uptake in isolated EDL muscles, and the maximal increase was threefold over basal levels at a concentration of 600 µmol/l H₂O₂. H₂O₂-stimulated 2-DG uptake was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, but not the nitric oxide inhibitor N^G-monomethyl-L-arginine. H₂O₂ stimulated the phosphorylation of Akt Ser⁴⁷³ (7-fold) and Thr³⁰⁸ (2-fold) in isolated EDL muscles. H₂O₂ at 600 µmol/l had no effect on ATP concentrations and did not increase the activities of either the 1 or 2 catalytic isoforms of AMP-activated protein kinase. These results demonstrate that acute exposure of muscle to ROS is a potent stimulator of skeletal muscle glucose uptake and that this occurs through a PI3K-dependent mechanism.

hydrogen peroxide; Akt phosphorylation; adenosine monophosphate-activated protein kinase

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