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.

Effect of Angiotensin (1-7) on Heart Function in an Experimental Rat Model of Obesity

“…In contrast to the present study, Ferreira et al showed an improved cardiac function, indicated by elevated dp/dt anddp/dt and furthermore, an attenuation of the isoproterenolinduced cardiac fibrosis in transgenic rats. Previous studies also indicated an antifibrotic action of Ang(1-7) in vitro and in vivo (Santos et al, 2004;Ferreira et al, 2010;Dong et al, 2012;McCollum et al, 2012;Acuña et al, 2014). In contrast to these findings, the present study revealed no antifibrotic effect of Ang(1-7) in a transgenic rat model.…”

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Fibrous tissues may prevent normal tissue recovery, particularly in the muscle where fibrosis has been shown to lead to progressive skeletal muscle injury, for example in Duchenne's muscular dystrophy (Acuna et al, 2014). Previous work has suggested that PDGFRβ+ pericytes contribute to scar formation (Arimura et al, 2012) and express fibroblast-associated markers (such as collagen IV, fibronectin and fibroblast surface proteins).…”

The complex of PAMAM-OH dendrimer with Angiotensin (1–7) prevented the disuse-induced skeletal muscle atrophy in mice

“…However, the instability of Ang-(1-7) restricts efficient oral or injected administration. 11,19 A new delivery method is needed that increases the half-life and improves the bioavailability of this peptide in target tissues.…”