Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle

Abstract

New findings r What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities? r What is the main finding and its importance?Angiotensin II induces skeletal muscle abnormalities and reduced exercise capacity. Mitochondrial dysfunction and a decreased number of oxidative fibres are manifest early, while muscle atrophy is seen later. Thus, angiotensin II may play an important role in the skeletal muscle abnormalities observed in a wide variety of diseases.Skeletal muscle abnormalities, such as mitochondrial dysfunction, a decreased percentage of oxidative fibres and atrophy, are the main cause of reduced exercise capacity observed in ageing and various diseases, including heart failure. The renin-angiotensin system, particularly angiotensin II (Ang II), is activated in the skeletal muscle in these conditions. Here, we examined whether Ang II could directly induce these skeletal muscle abnormalities and investigated their time course. Angiotensin II (1000 ng kg −1 min −1 ) or vehicle was administered to male C57BL/6J mice (10-12 weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4 weeks. Angiotensin II significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4 weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4 weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with Ang II. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with Ang II at 1 and 4 weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complex I and complex III activities were significantly decreased in the skeletal muscle from mice treated Ang II at 1 and 4 weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that type I fibres were decreased and type IIb fibres increased in mice treated with Ang II at 1 week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with Ang II at 4 weeks. Thus, Ang II could directly induce the abnormalities in skeletal muscle function and structure.

Angiotensin-II-induced Muscle Wasting is Mediated by 25-Hydroxycholesterol via GSK3β Signaling Pathway

“…Inactivation of GSK-3β facilitates recovery of mitochondria potential by suppressing ROS production, leading to cytoprotection from oxidant stress-induced cell death (Sunaga et al, 2014). Along this line, ang II infusion was shown to induce ROS production and mitochondria dependent apoptosis in mouse skeletal muscle (Kadoguchi et al, 2015). Bad is an important protein involved in mitochondrial dependent apoptosis.…”

Cytokine Signaling in Skeletal Muscle Wasting

“…Muscle-specific knockout of PKD1 prevented ang II-induced wasting. A second study [47] showed that mitochondrial oxidative enzymes were significantly decreased, while superoxide production was increased, in the skeletal muscle of ang II-treated mice.…”

Skeletal muscle bioenergetics in aging and heart failure

“…Heart failure is associated with increased circulating ANG II [108,109]. Chronic infusion with ANG II leads to muscle atrophy through increase muscle protein degradation and apoptosis [108], reduced exercise tolerance, and impaired mitochondrial function [110]. In a mouse model of high fat diet induced type 2 diabetes blocking ANG II receptors improved both mitochondrial function and exercise capacity, which supports a causal role for elevated ANG II in skeletal muscle mitochondrial dysfunction in heart disease [111].…”