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

Tomoyasu Kadoguchi, Shintaro Kinugawa, Shingo Takada, Arata Fukushima, Takaaki Furihata, Tsuneaki Homma, Yoshihiro Masaki, Wataru Mizushima, Mikito Nishikawa, Masashige Takahashi, Takashi Yokota, Shouji Matsushima, Koichi Okita, Hiroyuki Tsutsui

Research output: Contribution to journalArticle

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Abstract

New findings: 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.

Original languageEnglish
Pages (from-to)312-322
Number of pages11
JournalExperimental Physiology
Volume100
Issue number3
DOIs
Publication statusPublished - Mar 1 2015
Externally publishedYes

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Hindlimb
Angiotensin II
Atrophy
Skeletal Muscle
Citrate (si)-Synthase
Muscles
Glycogen Synthase
Muscular Atrophy
NADPH Oxidase
Electron Transport Complex III
Renin-Angiotensin System
Exercise Test
Inbred C57BL Mouse
Superoxides
Caspase 3
Running
NAD
Heart Failure
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle. / Kadoguchi, Tomoyasu; Kinugawa, Shintaro; Takada, Shingo; Fukushima, Arata; Furihata, Takaaki; Homma, Tsuneaki; Masaki, Yoshihiro; Mizushima, Wataru; Nishikawa, Mikito; Takahashi, Masashige; Yokota, Takashi; Matsushima, Shouji; Okita, Koichi; Tsutsui, Hiroyuki.

In: Experimental Physiology, Vol. 100, No. 3, 01.03.2015, p. 312-322.

Research output: Contribution to journalArticle

Kadoguchi, T, Kinugawa, S, Takada, S, Fukushima, A, Furihata, T, Homma, T, Masaki, Y, Mizushima, W, Nishikawa, M, Takahashi, M, Yokota, T, Matsushima, S, Okita, K & Tsutsui, H 2015, 'Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle', Experimental Physiology, vol. 100, no. 3, pp. 312-322. https://doi.org/10.1113/expphysiol.2014.084095
Kadoguchi, Tomoyasu ; Kinugawa, Shintaro ; Takada, Shingo ; Fukushima, Arata ; Furihata, Takaaki ; Homma, Tsuneaki ; Masaki, Yoshihiro ; Mizushima, Wataru ; Nishikawa, Mikito ; Takahashi, Masashige ; Yokota, Takashi ; Matsushima, Shouji ; Okita, Koichi ; Tsutsui, Hiroyuki. / Angiotensin II can directly induce mitochondrial dysfunction, decrease oxidative fibre number and induce atrophy in mouse hindlimb skeletal muscle. In: Experimental Physiology. 2015 ; Vol. 100, No. 3. pp. 312-322.
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