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 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-beta 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-beta 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.