title: Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle.
abstract: What is the central question of this study? Does angiotensin II directly induce skeletal muscle abnormalities? 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.
authors.affiliation: Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita-ku, Hokkaido, Sapporo, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Kadoguchi
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kinugawa
authors.forename: Shingo
authors.initials: S
authors.lastname: Takada
authors.forename: Arata
authors.initials: A
authors.lastname: Fukushima
authors.forename: Takaaki
authors.initials: T
authors.lastname: Furihata
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Homma
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Masaki
authors.forename: Wataru
authors.initials: W
authors.lastname: Mizushima
authors.forename: Mikito
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Masashige
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokota
authors.forename: Shouji
authors.initials: S
authors.lastname: Matsushima
authors.forename: Koichi
authors.initials: K
authors.lastname: Okita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsutsui
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D004253:DNA Nucleotidylexotransferase / Q000378:metabolism; D006614:Hindlimb / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009133:Muscular Atrophy / Q000139:chemically induced* / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects*; D012084:Renin-Angiotensin System / Q000187:drug effects
chemical_list: D009124:Muscle Proteins; D000804:Angiotensin II; D000803:Angiotensin I; D019255:NADPH Oxidases; D004253:DNA Nucleotidylexotransferase; D053148:Caspase 3