Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice
Charlotte Bonnard, … , Hubert Vidal, Jennifer Rieusset
Charlotte Bonnard, … , Hubert Vidal, Jennifer Rieusset
Published January 10, 2008
Citation Information: J Clin Invest. 2008;118(2):789-800. https://doi.org/10.1172/JCI32601.
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Research Article Metabolism

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

Abstract

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.

Authors

Charlotte Bonnard, Annie Durand, Simone Peyrol, Emilie Chanseaume, Marie-Agnes Chauvin, Béatrice Morio, Hubert Vidal, Jennifer Rieusset

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Figure 7

ROS-induced mitochondrial alterations in C2C12 muscle cells.

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ROS-induced mitochondrial alterations in C2C12 muscle cells. ...
(A) ROS production, measured by NBT reduction, in differentiated C2C12 myotubes incubated with glucose (25 mM) or palmitate (200 μM) in the presence or absence of NAC (10 mM) for 96 hours (n = 4). Data are expressed relative to the respective control (dotted line). (B) Effect of H2O2 (0.1 mM), glucose (25 mM), and palmitate (200 μM) on mtDNA levels in differentiated C2C12 myotubes. Myotubes were treated for 96 hours in the presence or absence of 10 mM NAC (n = 4). Data are expressed relative to the control condition (dotted line). (C) CS activity measured in total lysates of myotubes treated for 96 hours with H2O2 (0.1 mM), glucose (25 mM), or palmitate (200 μM) in the presence or absence of NAC (10 mM) (n = 4). (D) mRNA levels of POLG2, SSBP1, and PGC1α genes determined by quantitative RT-PCR in H2O2-, glucose-, or palmitate-treated myotubes in the presence or absence of NAC for 96 hours (n = 4). All results are expressed as fold change relative to the values of untreated cells set to 1 unit (dotted line). *P < 0.05, **P < 0.01 vs. respective control; #P < 0.05 vs. without NAC.