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This Article Full Text Full Text (PDF) Buy All Versions of this Article: 297/3/H1069    most recent 00267.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yokota, T. Articles by Tsutsui, H. PubMed PubMed Citation Articles by Yokota, T. Articles by Tsutsui, H.

Oxidative stress in skeletal muscle impairs mitochondrial respiration and limits exercise capacity in type 2 diabetic mice

¹Department of Cardiovascular Medicine, ²Department of Neurosurgery, ³Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo; ⁴Third Department of Internal Medicine, Osaka Medical College; and ⁵Graduate School of Program in Lifelong Learning Studies, Hokusho University, Ebetsu, Japan

Submitted 18 March 2009 ; accepted in final form 13 July 2009

Insulin resistance or diabetes is associated with limited exercise capacity, which can be caused by the abnormal energy metabolism in skeletal muscle. Oxidative stress is involved in mitochondrial dysfunction in diabetes. We hypothesized that increased oxidative stress could cause mitochondrial dysfunction in skeletal muscle and make contribution to exercise intolerance in diabetes. C57/BL6J mice were fed on normal diet or high fat diet (HFD) for 8 wk to induce obesity with insulin resistance and diabetes. Treadmill tests with expired gas analysis were performed to determine the exercise capacity and whole body oxygen uptake (O₂). The work (vertical distance x body weight) to exhaustion was reduced in the HFD mice by 36%, accompanied by a 16% decrease of peak O₂. Mitochondrial ADP-stimulated respiration, electron transport chain complex I and III activities, and mitochondrial content in skeletal muscle were decreased in the HFD mice. Furthermore, superoxide production and NAD(P)H oxidase activity in skeletal muscle were significantly increased in the HFD mice. Intriguingly, the treatment of HFD-fed mice with apocynin [10 mmol/l; an inhibitor of NAD(P)H oxidase activation] improved exercise intolerance and mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism itself. The exercise capacity and mitochondrial function in skeletal muscle were impaired in type 2 diabetes, which might be due to enhanced oxidative stress. Therapies designed to regulate oxidative stress and maintain mitochondrial function could be beneficial to improve the exercise capacity in type 2 diabetes.

exercise intolerance; insulin resistance; mitochondrial function; oxygen uptake; superoxide