Pflügers Archiv - European Journal of Physiology

, Volume 467, Issue 9, pp 1975–1984 | Cite as

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

  • Carla Meneses
  • María Gabriela Morales
  • Johanna Abrigo
  • Felipe Simon
  • Enrique Brandan
  • Claudio Cabello-VerrugioEmail author
Muscle physiology


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.


Angiotensin Muscle wasting Apoptosis Proteasome 



Angiotensin II

Ang (1–7)

Angiotensin 1–7


Angiotensin-converting enzyme


Renin-angiotensin system


Ubiquitin proteasome pathway



The authors thank Darling Vera for the technical assistance.


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).

Conflict of interest

The authors confirm that there are no conflicts of interest.

Supplementary material

424_2014_1617_Fig6_ESM.gif (674 kb)
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)

424_2014_1617_MOESM1_ESM.tif (13.7 mb)
High Resolution Image (TIFF 13988 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Carla Meneses
    • 1
  • María Gabriela Morales
    • 1
  • Johanna Abrigo
    • 1
  • Felipe Simon
    • 2
    • 3
  • Enrique Brandan
    • 4
  • Claudio Cabello-Verrugio
    • 1
    • 5
    Email author
  1. 1.Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Facultad de MedicinaUniversidad Andres BelloSantiagoChile
  2. 2.Laboratorio de Fisiopatología Integrativa, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Facultad de MedicinaUniversidad Andres BelloSantiagoChile
  3. 3.Millennium Institute on Immunology and ImmunotherapySantiagoChile
  4. 4.Centro de Regulación Celular y Patología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Laboratorio de Diferenciación Celular y Patología, Departamento de Biología Celular y Molecular, MIFABPontificia Universidad Católica de ChileSantiagoChile
  5. 5.Claudio Cabello-Verrugio. Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas y Facultad de MedicinaUniversidad Andres BelloSantiagoChile

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