Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling

María José Acuña, Patrizia Pessina, Hugo Olguin, Daniel Cabrera, Carlos P. Vio, Michael Bader, Pura Muñoz-canoves, Robson A. Santos, Claudio Cabello-verrugio, Enrique Brandan

Resultado de la investigación: Contribución a una revistaArtículo

91 Citas (Scopus)

Resumen

Duchenne muscular dystrophy (DMD) is the most common inherited neuromuscular disease, and is characterized by the lack of dystrophin, muscle wasting, increased transforming growth factor (TGF)-β Smad-dependent signalling and fibrosis. Acting via the Mas receptor, angiotensin-1-7 [Ang-(1-7)], is part of the renin-angiotensin system, with the opposite effect to that of angiotensin II. We hypothesized that the Ang-(1-7)/Mas receptor axis might protect chronically damaged tissues as in skeletal muscle of the DMD mouse model mdx. Infusion or oral administration of Ang-(1-7) in mdx mice normalized skeletal muscle architecture, decreased local fibrosis and improved muscle function in vitro and in vivo. These positive effects were mediated by the inhibition of TGF-β Smad signalling, which in turn led to reduction of the pro-fibrotic microRNA miR-21 concomitant with a reduction in the number of TCF4 expressing fibroblasts. Mdx mice infused with Mas antagonist (A-779) and mdx deficient for the Mas receptor showed highly deteriorated muscular architecture, increased fibrosis and TGF-β signalling with diminished muscle strength. These results suggest that this novel compound Ang-(1-7) might be used to improve quality of life and delay death in individuals with DMD and this drug should be investigated in further pre-clinical trials.

Idioma originalInglés
Número de artículoddt514
Páginas (desde-hasta)1237-1249
Número de páginas13
PublicaciónHuman Molecular Genetics
Volumen23
N.º5
DOI
EstadoPublicada - 1 mar 2014

Áreas temáticas de ASJC Scopus

  • Genética
  • Genética (clínica)
  • Biología molecular

Huella Profundice en los temas de investigación de 'Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling'. En conjunto forman una huella única.

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    Acuña, M. J., Pessina, P., Olguin, H., Cabrera, D., Vio, C. P., Bader, M., Muñoz-canoves, P., Santos, R. A., Cabello-verrugio, C., & Brandan, E. (2014). Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. Human Molecular Genetics, 23(5), 1237-1249. [ddt514]. https://doi.org/10.1093/hmg/ddt514