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OBJECTIVE-Blockade of angiotensin (Ang) II has been shown to prevent new-onset type 2 diabetes. We focused on the effects of Angli on muscle mitochondria, especially on their biogenesis, as an underlining mechanism of type 2 diabetes.
RESEARCH DESIGN AND METHODS-C2C12 cells and C57bl/6 mice were used to examine roles for Angli in the regulation of muscle mitochondria and to explore whether the effect was mediated by type 1 Angli receptor (ATlR) or type 2 receptor (AT2R).
RESULTS-C2C12 cells treated with 10^sup -8^-10^sub -6^ mol/l AngII reduced the mitochondrial content associated with downregulation of the genes involved in mitochondrial biogenesis. The action of AngII was diminished by blockade of AT2R but not ATIR, whereas overexpression of AT2R augmented the effect. AngII increased mitochondrial ROS and decreased mitochondrial membrane potential, and these effects of AngII were significantly suppressed by blockade of either ATIR or AT2R. Chronic AngII infusion in mice also reduced muscle mitochondrial content in association with increased intramuscular triglyceride and deteriorated glycemic control. The AngII-induced reduction in muscle mitochondria in mice was partially, but significantly, reversed by blockade of either ATIR or AT2R, associated with increased fat oxidation, decreased muscle triglyceride, and improved glucose tolerance. Genes involved in mitochondrial biogenesis were decreased via AT2R but not ATIR under these in vivo conditions.
CONCLUSIONS-Taken together, these findings imply the novel roles for AngII in the regulation of muscle mitochondria and lipid metabolism. Angli reduces mitochondrial content possibly through ATIR-dependent augmentation of their degradation and AT2R-dependent direct suppression of their biogenesis. Diabetes 58:710-717, 2009
Recent studies have shown that mitochondrial content and function are significantly reduced in the skeletal muscle of patients with type 2 diabetes (1,2). Percutaneous biopsy of vastus lateralis muscle has revealed that subsarcolemmal mito- chondria, which are believed to be crucial for glucose transport and fatty acid oxidation, were decreased in type 2 diabetic patients, compared with body weight-matched nondiabetic patients (2). Moreover, reduced mitochondrial content and function in muscle have been also observed in pre-diabetic subjects with a family history of type 2 diabetes (3). Recent microarray analyses have revealed that expression of genes involved in mitochondrial biogenesis and oxidative phosphorylation is coordinately decreased in the skeletal muscle of patients with type 2 diabetes (4,5), for example, peroxisome proliferator-activator receptor -y...