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

TLDR

Mitochondrial dysfunction in skeletal muscle is linked to type 2 diabetes, yet it remains unclear whether it causes or follows insulin resistance. The study examined muscle mitochondrial structure and function during the onset of insulin resistance and progression to diabetes in mice fed a high‑fat, high‑sucrose diet. The authors assessed oxidative stress by measuring ROS production in skeletal muscle of diet‑induced diabetic mice, linking it to mitochondrial abnormalities. Glucose intolerance appeared after one month of diet without mitochondrial dysfunction, but prolonged feeding induced diabetes with altered mitochondrial biogenesis, structure, and function driven by increased ROS, which was reversed by glycemic control or antioxidant treatment, showing ROS‑mediated mitochondrial changes arise after insulin resistance.

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.