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The angiotensin-(1–7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice

  • Muscle physiology
  • Published:
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Abstract

Angiotensin-(1–7) [Ang (1–7)] is a peptide belonging to the non-classical renin-angiotensin system (RAS). Ang (1–7), through its receptor Mas, has an opposite action to angiotensin II (Ang II), the typical peptide of the classical RAS axis. Ang II produces skeletal muscle atrophy, a pathological condition characterised by the loss of strength and muscle mass. A feature of muscle atrophy is the decrease of the myofibrillar proteins produced by the activation of the ubiquitin-proteasome pathway (UPP), evidenced by the increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. In addition, it has been described that Ang II also induces myonuclear apoptosis during muscle atrophy. We assessed the effects of Ang (1–7) and Mas participation on myonuclear apoptosis during skeletal muscle atrophy induced by Ang II. Our results show that Ang (1–7), through Mas, prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm (increased apoptotic nuclei, increased expression of caspase-8 and caspase-9, increased caspase-3 activity and increased Bax/Bcl-2 ratio). Concomitantly, Ang (1–7) also attenuates the decrease in fibre diameter and muscle strength, and prevents the increase in atrogin-1 and MuRF-1 during the muscle wasting induced by Ang II. Interestingly, these effects of Ang (1–7) are dependent on the Mas receptor. Thus, we demonstrated for the first time that Ang (1–7) prevents myonuclear apoptosis during the recovery of skeletal muscle atrophy induced by Ang II.

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Abbreviations

AngII:

Angiotensin II

Ang (1–7):

Angiotensin 1–7

ACE:

Angiotensin-converting enzyme

RAS:

Renin-angiotensin system

UPP:

Ubiquitin proteasome pathway

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Acknowledgments

The authors thank Darling Vera for the technical assistance.

Funding

This study was supported by research grants from Association-Francaise Contre Les Myopathies AFM 16670 (CCV); FONDECYT 1120380 (CCV), 3130593 (MGM), 1121078 (FS), 1110426 (EB); Millennium Institute on Immunology and Immunotherapy, P09-016-F (FS); CARE PFB12/2007 (EB), Fundación Chilena para Biología Celular Proyecto MF-100; UNAB-DI-281-13/R (CCV).

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Correspondence to Claudio Cabello-Verrugio.

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Fig. S1

Angiotensin-(1–7) reverts the decrease of fiber diameter in the diaphragm during muscle wasting induced by angiotensin II. C57BL10 mice were systemically treated with the vehicle (a), Ang II (b), Ang (1–7) (c), Ang II + Ang (1–7) (d), A779 (e), or Ang II + Ang (1–7) + A779 (f) for 14 days as described in the Materials and Methods section. Haematoxylin and eosin staining was performed on cryosections of the diaphragm. The images are representative of three independent experiments, using four mice for each experimental condition. The bar corresponds to 50 μm. (GIF 673 kb)

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Meneses, C., Morales, M.G., Abrigo, J. et al. The angiotensin-(1–7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice. Pflugers Arch - Eur J Physiol 467, 1975–1984 (2015). https://doi.org/10.1007/s00424-014-1617-9

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