Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice

• Published in: The Journal of clinical investigation 2008-02, Vol.118 (2), p.789-800
• Main Authors: Bonnard, Charlotte, Durand, Annie, Peyrol, Simone, Chanseaume, Emilie, Chauvin, Marie-Agnes, Morio, Béatrice, Vidal, Hubert, Rieusset, Jennifer
• Format: Article
• Language: English
• Subjects: Animals; Biomedical research; Biosynthesis; Diabetes; Diabetes Mellitus, Type 2; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Diet; Dietary Fats; Dietary Fats - administration & dosage; Fatty acids; Food and Nutrition; Genetic aspects; Glucose; Health aspects; Insulin Resistance; Kinases; Life Sciences; Lipids; Male; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria, Muscle; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - ultrastructure; Mitochondrial Diseases; Mitochondrial Diseases - etiology; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Mitochondrial DNA; Muscle Fibers, Skeletal; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal; Muscle, Skeletal - metabolism; Muscle, Skeletal - ultrastructure; Muscles; Musculoskeletal system; Oils & fats; Oxidative Stress; Phosphorylation; Physiological aspects; Plasma; Reactive Oxygen Species; Reactive Oxygen Species - analysis; Reactive Oxygen Species - metabolism; Risk factors; Sucrose; Sucrose - administration & dosage
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci32601

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of type 2 diabetes. However, whether these changes are a cause or a consequence of insulin resistance is not clear. We investigated the structure and function of muscle mitochondria during the development of insulin resistance and progression to diabetes in mice fed a high-fat, high-sucrose diet. Although 1 month of high-fat, high-sucrose diet feeding was sufficient to induce glucose intolerance, mice showed no evidence of mitochondrial dysfunction at this stage. However, an extended diet intervention induced a diabetic state in which we observed altered mitochondrial biogenesis, structure, and function in muscle tissue. We assessed the role of oxidative stress in the development of these mitochondrial abnormalities and found that diet-induced diabetic mice had an increase in ROS production in skeletal muscle. In addition, ROS production was associated with mitochondrial alterations in the muscle of hyperglycemic streptozotocin-treated mice, and normalization of glycemia or antioxidant treatment decreased muscle ROS production and restored mitochondrial integrity. Glucose- or lipid-induced ROS production resulted in mitochondrial alterations in muscle cells in vitro, and these effects were blocked by antioxidant treatment. These data suggest that mitochondrial alterations do not precede the onset of insulin resistance and result from increased ROS production in muscle in diet-induced diabetic mice.