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

Abstract

OBJECTIVE— Blockade of angiotensin (Ang) II has been shown to prevent new-onset type 2 diabetes. We focused on the effects of AngII 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 AngII in the regulation of muscle mitochondria and to explore whether the effect was mediated by type 1 AngII receptor (AT1R) or type 2 receptor (AT2R). RESULTS— C2C12 cells treated with 10 −8 –10 −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 AT1R, 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 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.

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

“…However, in a model of IR associated with excessive RAS activation, impaired State 3 mitochondrial respiration was observed in mouse skeletal muscle (Takada et al 2013). Moreover, in mouse skeletal muscles, chronic Ang II infusion caused glucose intolerance and mitochondrial abnormalities together with increased mitochondrial ROS generation (Mitsuishi et al 2009). …”

p66Shc mediates high-glucose and angiotensin II-induced oxidative stress renal tubular injury via mitochondrial-dependent apoptotic pathway

“…The major source of ROS is believed to be the mitochondrial electron transport system (13). In addition, many factors, such as ischemic renal injury (6), advanced glycation end products (5), angiotensin II (ANG II) (25,36), besides HG (14), may also induce excessive ROS production and mitochondrial dysfunction, which eventually leads to apoptosis and necrosis of the renal tubular cells (35). Our laboratory's previous studies have shown that HG can reduce the mitochondrial membrane potential (⌬m) and enhance the release of mitochondrial cytochrome c (mCyt.C) into the cytosol with activation of caspases and ultimately apoptosis in tubular cells (32).…”

Postprandial fatty acid uptake and adipocyte remodeling in angiotensin type 2 receptor-deficient mice fed a high-fat/high-fructose diet

“…24 Another explanation would be an increase in fatty acid release from visceral adipose tissue. When compared to WT mice, the AT2R-KO mice did not display any change in glucose tolerance, circulating NEFA and triglycerides levels, in accordance with the known relative resistance of mice vs. rats to diet-induced insulin resistance.…”