Angiotensin II Reduces Mitochondrial Content in Skeletal Muscle and Affects Glycemic Control

Abstract

Objective. Blockade of angiotensin II (AngII) has been shown to prevent new-onset of type2 diabetes mellitus (T2DM). We focused on the effects of AngII on muscle mitochondria, especially on their biogenesis, as an underlining mechanism of T2DM.

Research Design and Methods. C2C12 cells and C57bl/6 mice were used to examine roles for AngII in the regulation of muscle mitochondria and to explore whether the effect was mediated by type1 AngII receptor (AT1R) or type2 receptor (AT2R).

Results. C2C12 cells treated with 10^−8∼−6 mol/l AngII reduced the mitochondrial content associated with down-regulation of the genes involved in mitochondrial biogenesis. The action of AngII was diminished by blockade of AT2R but not AT1R, while over-expression 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 AT1R 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 AT1R 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 AT1R 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. AngII reduces mitochondrial content possibly through AT1R-dependent augmentation of their degradation, and AT2R-dependent direct suppression of their biogenesis.