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Different effects of the deletion of angiotensin converting enzyme 2 and chronic activation of the renin-angiotensin system on muscle weakness in middle-aged mice

Hypertension Research volume 43, pages 296–304 (2020)Cite this article

Abstract

Inhibition of the renin-angiotensin system (RAS) has been shown to alleviate muscle atrophy both under pathological conditions and during physiological aging. We recently reported that the deletion of angiotensin converting enzyme 2 (ACE2), which converts Angiotensin II to Angiotensin-(1–7) in mice, leads to the early manifestation of aging-associated muscle weakness along with the increased expression of p16INK4a, a senescence-associated gene, and increased central nuclei in the tibialis anterior (TA) muscle in middle age. As ACE2 is multifunctional and functions beyond its role in the RAS, we investigated whether activation of the RAS primarily contributes to muscle weakness in ACE2 knockout (KO) mice by comparing these mice to Tsukuba hypertensive (TH) mice that overproduce human angiotensin II. The grip strength of young (6 months) and middle-aged (15 months) TH mice was consistently lower than that of wild-type mice at the same ages. Middle-aged TH mice were continuously lean with extremely reduced adiposity. Central nuclei in the gastrocnemius (GM) muscle were increased in ACE2KO mice, while no apparent morphological change was observed in the GM muscles of TH mice. Increased expression of p16INK4a along with alterations in the expression of several sarcopenia-associated genes were observed in the GM muscles of ACE2KO mice but not TH mice. These findings suggest that chronic overactivation of the RAS does not primarily contribute to the early aging phenotypes of skeletal muscle in ACE2KO mice.

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Acknowledgements

We are most grateful to Hikari Kitamura, Yuka Nakao, Yoshinori Koishi, and Tomoko Sato for their excellent technical assistance.

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Authors and Affiliations

  1. Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Hikari Takeshita, Koichi Yamamoto, Satoko Nozato & Hiromi Rakugi

  2. Department of Pharmacology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan

    Masaki Mogi

  3. Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Toon, Ehime, Japan

    Masatsugu Horiuchi

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  1. Hikari Takeshita
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Correspondence to Koichi Yamamoto.

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Takeshita, H., Yamamoto, K., Mogi, M. et al. Different effects of the deletion of angiotensin converting enzyme 2 and chronic activation of the renin-angiotensin system on muscle weakness in middle-aged mice. Hypertens Res 43, 296–304 (2020). https://doi.org/10.1038/s41440-019-0375-7

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