Restoration of muscle strength in dystrophic muscle by Angiotensin-1-7 through inhibition of TGF-β signaling

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Item Type:	Article
Title:	Restoration of muscle strength in dystrophic muscle by Angiotensin-1-7 through inhibition of TGF-β signaling
Creators Name:	Acuna, M.J., Pessina, P., Olguin, H., Cabrera, D., Vio, C.P., Bader, M., Munoz-Canoves, P., Santos, R.A., Cabello-Verrugio, C. and Brandan, E.
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)-{beta} Smad dependent signaling 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 protects 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-{beta} Smad signaling, 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-{beta} signaling 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.
Keywords:	Angiotensin I, Animal Disease Models, Cell Surface Receptors, Duchenne Muscular Dystrophy, Extracellular Matrix, Fibroblasts, Fibrosis, MicroRNAs, Muscle Strength, Peptide Fragments, Signal Transduction, Skeletal Muscle, Transforming Growth Factor beta, Animals, Mice
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	23
Number:	5
Page Range:	1237-1249
Date:	1 March 2014
Official Publication:	https://doi.org/10.1093/hmg/ddt514
PubMed:	View item in PubMed

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