title: Restoration of muscle strength in dystrophic muscle by angiotensin-1-7 through inhibition of TGF-β signalling.
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.
authors.affiliation: Center for Aging and Regeneration, CARE Chile UC and Department Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, Santiago, Chile.
authors.forename: María José
authors.initials: MJ
authors.lastname: Acuña
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pessina
authors.forename: Hugo
authors.initials: H
authors.lastname: Olguin
authors.forename: Daniel
authors.initials: D
authors.lastname: Cabrera
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Vio
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Pura
authors.initials: P
authors.lastname: Muñoz-Canoves
authors.forename: Robson A
authors.initials: RA
authors.lastname: Santos
authors.forename: Claudio
authors.initials: C
authors.lastname: Cabello-Verrugio
authors.forename: Enrique
authors.initials: E
authors.lastname: Brandan
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; C105154:angiogenin receptor; D000803:Angiotensin I; C118790:angiotensin I (1-7)