Angiotensin-(1-7) attenuates disuse skeletal muscle atrophy in mice via its receptor, Mas

• Published in: Disease models & mechanisms Vol. 9; no. 4; pp. 441 - 449
• Main Authors: Morales, María Gabriela, Abrigo, Johanna, Acuña, María José, Santos, Robson A, Bader, Michael, Brandan, Enrique, Simon, Felipe, Olguin, Hugo, Cabrera, Daniel, Cabello-Verrugio, Claudio
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.04.2016; The Company of Biologists
• Subjects: Angiotensin I - pharmacology; Angiotensin I - therapeutic use; Angiotensin-(1-7); Animals; Atrophy; Disuse; Experiments; Insulin-Like Growth Factor I - metabolism; Insulin-like growth factors; Isometric Contraction - drug effects; Kinases; Male; Mas receptor; Mice; Mice, Inbred C57BL; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - pathology; Muscle Proteins - metabolism; Muscle strength; Muscle Strength - drug effects; Muscular Atrophy - drug therapy; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular Atrophy - physiopathology; Muscular Disorders, Atrophic - drug therapy; Muscular Disorders, Atrophic - metabolism; Muscular Disorders, Atrophic - pathology; Muscular Disorders, Atrophic - physiopathology; Musculoskeletal system; Myosin Heavy Chains - metabolism; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Peptides; Phosphorylation; Proteasomes; Protein synthesis; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - metabolism; Receptors, G-Protein-Coupled - metabolism; Signal Transduction - drug effects; Skeletal muscle; SKP Cullin F-Box Protein Ligases - metabolism; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - metabolism; Atrophy; Mas receptor; Angiotensin-(1-7); Disuse; Skeletal muscle
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.023390

Immobilization is a form of disuse characterized by a loss of strength and muscle mass. Among the main features are decreased IGF-1/Akt signalling and increased ubiquitin-proteasome pathway signalling, which induce greater myosin heavy chain degradation. Activation of the classical renin-angiotensin system (RAS) causes deleterious effects in skeletal muscle, including muscle wasting. In contrast, angiotensin-(1-7) [Ang-(1-7)], a peptide of the non-classical RAS, produces beneficial effects in skeletal muscle. However, the role of Ang-(1-7) in skeletal muscle disuse atrophy and independent of classical RAS activation has not been evaluated. Therefore, we assessed the functions of Ang-(1-7) and the Mas receptor in disuse muscle atrophyin vivousing unilateral cast immobilization of the hind limb in male, 12-week-old wild-type (WT) and Mas-knockout (Mas KO) mice for 1 and 14 days. Additionally, we evaluated the participation of IGF-1/IGFR-1/Akt signalling and ubiquitin-proteasome pathway expression on the effects of Ang-(1-7) immobilization-induced muscle atrophy. Our results found that Ang-(1-7) prevented decreased muscle strength and reduced myofiber diameter, myosin heavy chain levels, and the induction of atrogin-1 and MuRF-1 expressions, all of which normally occur during immobilization. Analyses indicated that Ang-(1-7) increases IGF-1/IGFR-1/Akt pathway signalling through IGFR-1 and Akt phosphorylation, and the concomitant activation of two downstream targets of Akt, p70S6K and FoxO3. These anti-atrophic effects of Ang-(1-7) were not observed in Mas KO mice, indicating crucial participation of the Mas receptor. This report is the first to propose anti-atrophic effects of Ang-(1-7) via the Mas receptor and the participation of the IGF-1/IGFR-1/Akt/p70S6K/FoxO3 mechanism in disuse skeletal muscle atrophy.