Angiotensin-(1–7) decreases skeletal muscle atrophy induced by angiotensin II through a Mas receptor-dependent mechanism

Abstract

Skeletal muscle atrophy is a pathological condition characterized by the loss of strength and muscle mass, an increase in myosin heavy chain (MHC) degradation and increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. Angiotensin II (AngII) induces muscle atrophy. Angiotensin-(1–7) [Ang-(1–7)], through its receptor Mas, produces the opposite effects than AngII. We assessed the effects of Ang-(1–7) on the skeletal muscle atrophy induced by AngII. Our results show that Ang-(1–7), through Mas, prevents the effects induced by AngII in muscle gastrocnemius: the decrease in the fibre diameter, muscle strength and MHC levels and the increase in atrogin-1 and MuRF-1. Ang-(1–7) also induces AKT phosphorylation. In addition, our analysis in vitro using C₂C₁₂ myotubes shows that Ang-(1–7), through a mechanism dependent on Mas, prevents the decrease in the levels of MHC and the increase in the expression of the atrogin-1 and MuRF-1, both induced by AngII. Ang-(1–7) induces AKT phosphorylation in myotubes; additionally, we demonstrated that the inhibition of AKT with MK-2206 decreases the anti-atrophic effects of Ang-(1–7). Thus, we demonstrate for the first time that Ang-(1–7) counteracts the skeletal muscle atrophy induced by AngII through a mechanism dependent on the Mas receptor, which involves AKT activity. Our study indicates that Ang-(1–7) is novel molecule with a potential therapeutical use to improve muscle wasting associated, at least, with pathologies that present high levels of AngII.