Angiotensin II and skeletal muscle abnormalities

Abstract

Exercise capacity declines with chronic disease and age, and quality of life suffers. Skeletal muscle abnormalities are known to play important roles in this decline in exercise capacity. The many known skeletal muscle abnormalities include impairment of skeletal muscle energy metabolism, mitochondrial dysfunction in skeletal muscle, skeletal muscle cell apoptosis, a fibre-type transition from type I fibres to type II fibres, and skeletal muscle atrophy, all of which are thought to result in decreased exercise capacity. How do these skeletal muscle abnormalities observed with various chronic diseases and age occur? Might not some common factor exist? Based on previous research in heart muscle, the potential role of Ang II in the development of skeletal muscle abnormalities was investigated. One week after administering a pressor dose of Ang II (1000 ng kg−1 min−1) to mice, mitochondrial oxidative enzymes, such as citrate synthase activity, and mitochondrial complex activities in skeletal muscle had decreased, fewer type I fibres were present, and skeletal muscle cell apoptosis and NAD(P)H oxidase-derived reactive oxygen species (ROS) production had increased (Kadoguchi et al. 2015). These changes persisted until 4 weeks after administration of Ang II. Meanwhile, no apparent decreases in body weight, skeletal muscle mass or skeletal muscle cell cross-sectional area were seen after 1 week, but such decreases became obvious after 4 weeks. At that time, there was a decrease in phosphorylation of Akt and p70S6K, which are involved in protein synthesis, whereas atrogin-1 and MuRF-1, which are involved in protein degradation, increased (Kadoguchi et al. 2015). The same skeletal muscle abnormalities that are observed clinically were thus observed with Ang II administration to mice. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest in an early phase, and muscle atrophy is seen at a later phase of Ang II administration. This time-dependent progression of skeletal muscle abnormalities in Ang II-treated mice is also consistent with clinical observations. These things observed in skeletal muscle were originally studied in most cases in the heart. Angiotensin II binds to the angiotensin type 1 receptor (AT1R), a G protein-coupled receptor. This causes activation of NAD(P)H oxidase from activation of Gαq and leads to production of ROS. NAD(P)H oxidase-derived ROS have also been suggested to stimulate mitochondrial ROS, causing mitochondrial dysfunction. Dai et al. (2011) showed a relationship among Ang II, mitochondrial ROS and progression of cardiac hypertrophy and heart failure. Cardiac hypertrophy was first induced with administration of Ang II, causing an increase in mitochondrial ROS and damage to mitochondrial DNA in cardiac muscle cells. The cardiac hypertrophy, fibrosis and mitochondrial damage produced by Ang II were also found to be inhibited in mice with catalase overexpression in the mitochondria. Moreover, catalase overexpression in the mitochondria inhibited heart failure attributable to Gαq overexpression. Finally, they demonstrated that mitochondrial DNA defects attributable to pharmacological and genetic modification directly produce cardiac hypertrophy, fibrosis and heart failure. Our study could not demonstrate a causal relationship among various skeletal muscle abnormalities and activation of NAD(P)H oxidase and ROS (Kadoguchi et al. 2015), but the report of Dai et al. (2011) suggests that mitochondrial ROS induced by NAD(P)H oxidase-derived ROS attributable to Ang II may be involved in mitochondrial dysfunction even in skeletal muscle. Angiotensin II leads to weight loss. Angiotensin II causes breakdown of adipocytes by stimulating sympathetic nerve efferent pathways, and loss of appetite by inducing production of leptin from adipocytes. Our data (Kadoguchi et al. 2015) showed that Ang II also directly caused atrophy of the skeletal muscle, which suggests that AT1R is absent. On the contrary, AT1R blockers (ARBs) prevent weight gain. It has also been suggested that weight increases in a model of obesity from a high-fat diet can be inhibited by treatment with ARBs even in mice with AT1R deletion. These results suggest that the effects of Ang II or ARBs against body weight might occur independently of AT1R. Schuchard et al. (2015) focused on the role of the Mas receptor agonist angiotensin-(1–7) [Ang(1–7)], a metabolite of Ang II. Obesity, increased fat mass and the appearance of insulin resistance as a result of a high-fat diet were inhibited in rats that overexpressed Ang(1–7). The efficacy of ARB against obesity resulting from a high-fat diet disappeared with Mas receptor antagonists. The roles of ARB and Ang(1–7) in skeletal muscle are unclear; however, ARB treatment for skeletal muscle mitochondrial damage and atrophy not only eliminates ROS by inhibiting AT1R, but may also demonstrate efficacy via Ang(1–7). Moreover, skeletal muscle abnormalities may be treatable by Ang(1–7) itself. Skeletal muscle abnormalities in chronic diseases, such as cardiovascular disease and metabolic disease, and in advanced age have become a focus of interest in recent years, particularly in sarcopenia, which is characterized by skeletal muscle atrophy and mitochondrial dysfunction. Studies to elucidate the detailed mechanisms underlying these skeletal muscle abnormalities, particularly the roles of skeletal muscle mitochondrial ROS and the Ang II metabolite Ang(1–7), will be clinically significant.