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: Article

84 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 originalEnglish
Número de artículoddt514
Páginas (desde-hasta)1237-1249
Número de páginas13
PublicaciónHuman Molecular Genetics
Volumen23
N.º5
DOI
EstadoPublished - 1 mar 2014

Huella dactilar

Muscle Strength
Transforming Growth Factors
Inbred mdx Mouse
Duchenne Muscular Dystrophy
Muscles
Fibrosis
7-Ala-angiotensin (1-7)
Skeletal Muscle
Neuromuscular Diseases
Dystrophin
Renin-Angiotensin System
MicroRNAs
Angiotensin II
Oral Administration
Fibroblasts
Quality of Life
Clinical Trials
angiotensin I (1-7)
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Citar esto

Acuña, M. J., Pessina, P., Olguin, H., Cabrera, D., Vio, C. P., Bader, M., ... 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
Acuña, María José ; Pessina, Patrizia ; Olguin, Hugo ; Cabrera, Daniel ; Vio, Carlos P. ; Bader, Michael ; Muñoz-canoves, Pura ; Santos, Robson A. ; Cabello-verrugio, Claudio ; Brandan, Enrique. / Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. En: Human Molecular Genetics. 2014 ; Vol. 23, N.º 5. pp. 1237-1249.
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abstract = "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.",
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Acuña, MJ, Pessina, P, Olguin, H, Cabrera, D, Vio, CP, Bader, M, Muñoz-canoves, P, Santos, RA, 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, vol. 23, n.º 5, ddt514, pp. 1237-1249. https://doi.org/10.1093/hmg/ddt514

Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling. / Acuña, María José; Pessina, Patrizia; Olguin, Hugo; Cabrera, Daniel; Vio, Carlos P.; Bader, Michael; Muñoz-canoves, Pura; Santos, Robson A.; Cabello-verrugio, Claudio; Brandan, Enrique.

En: Human Molecular Genetics, Vol. 23, N.º 5, ddt514, 01.03.2014, p. 1237-1249.

Resultado de la investigación: Article

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T1 - Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling

AU - Acuña, María José

AU - Pessina, Patrizia

AU - Olguin, Hugo

AU - Cabrera, Daniel

AU - Vio, Carlos P.

AU - Bader, Michael

AU - Muñoz-canoves, Pura

AU - Santos, Robson A.

AU - Cabello-verrugio, Claudio

AU - Brandan, Enrique

PY - 2014/3/1

Y1 - 2014/3/1

N2 - 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.

AB - 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.

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U2 - 10.1093/hmg/ddt514

DO - 10.1093/hmg/ddt514

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