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

New findings What is the central question of this study? Does angiotensinII directly induce skeletal muscle abnormalities? What is the main finding and its importance? AngiotensinII 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, angiotensinII 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 angiotensinII (AngII), is activated in the skeletal muscle in these conditions. Here, we examined whether AngII could directly induce these skeletal muscle abnormalities and investigated their time course. AngiotensinII (1000ngkg(-1)min(-1)) or vehicle was administered to male C57BL/6J mice (10-12weeks of age) via subcutaneously implanted osmotic minipumps for 1 or 4weeks. AngiotensinII significantly decreased body and hindlimb skeletal muscle weights compared with vehicle at 4weeks. In parallel, muscle cross-sectional area was also decreased in the skeletal muscle at 4weeks. Muscle RING finger-1 and atrogin-1 were significantly increased in the skeletal muscle from mice treated with AngII. In addition, cleaved caspase-3 and terminal deoxynucleotidyl trasferase-mediated dUTP nick-positive nuclei were significantly increased in mice treated with AngII at 1 and 4weeks, respectively. Mitochondrial oxidative enzymes, such as citrate synthase, complexI and complexIII activities were significantly decreased in the skeletal muscle from mice treated AngII at 1 and 4weeks. NAD(P)H oxidase-derived superoxide production was increased. NADH staining revealed that typeI fibres were decreased and typeIIb fibres increased in mice treated with AngII at 1week. The work and running distance evaluated by a treadmill test were significantly decreased in mice treated with AngII at 4weeks. Thus, AngII could directly induce the abnormalities in skeletal muscle function and structure.