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Possible involvement of the 1 isoform of 5'AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle

¹Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502; ²Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507; ³Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501; and ⁴Department of Food Sciences and Nutritional Health, Kyoto Prefectural University, Kyoto 606-8522, Japan

Submitted 29 October 2003 ; accepted in final form 9 March 2004

Recent studies have suggested that 5'AMP-activated protein kinase (AMPK) is activated in response to metabolic stresses, such as contraction, hypoxia, and the inhibition of oxidative phosphorylation, which leads to insulin-independent glucose transport in skeletal muscle. In the present study, we hypothesized that acute oxidative stress increases the rate of glucose transport via an AMPK-mediated mechanism. When rat epitrochlearis muscles were isolated and incubated in vitro in Krebs buffer containing the oxidative agent H₂O₂, AMPK1 activity increased in a time- and dose-dependent manner, whereas AMPK2 activity remained unchanged. The activation of AMPK1 was associated with phosphorylation of AMPK Thr¹⁷², suggesting that an upstream kinase is involved in the activation process. H₂O₂-induced AMPK1 activation was blocked in the presence of the antioxidant N-acetyl-L-cysteine (NAC), and H₂O₂ significantly increased the ratio of oxidized glutathione to glutathione (GSSG/GSH) concentrations, a sensitive marker of oxidative stress. H₂O₂ did not cause an increase in the conventional parameters of AMPK activation, such as AMP and AMP/ATP. H₂O₂ increased 3-O-methyl-D-glucose transport, and this increase was partially, but significantly, blocked in the presence of NAC. Results were similar when the muscles were incubated in a superoxide-generating system using hypoxanthine and xanthine oxidase. Taken together, our data suggest that acute oxidative stress activates AMPK1 in skeletal muscle via an AMP-independent mechanism and leads to an increase in the rate of glucose transport, at least in part, via an AMPK1-mediated mechanism.

contraction; epitrochlearis muscle; hydrogen peroxide; hypoxanthine; xanthine oxidase

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