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.

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

“…In this context, Ang-(1-7) has a demonstrated anti-atrophic effect on Ang-II-dependent and -independent models, such as in disuse, sepsis, or Ang-II-induced cachexia. 11,[15][16][17][18] This study is highly relevant for muscle biology, particularly with regard to pathological statuses that induce muscle atrophy, such as sepsis, that cannot be treated with oral drug therapies or exercise. Therefore, further studies should be conducted to assess the therapeutic …”

“…For IP treatment, 50 µL of phosphate-buffered saline (PBS), Ang-(1-7) (0.8 mM), PAMAM-OH (0.4 mM), and the complex Ang-(1-7)/PAMAM-OH (2:1) were IP injected three times a week starting 24 h before cast immobilization. For osmotic pump delivery, PBS, Ang-(1-7) (100 ng/kg/min), PAMAM-OH (1 ng/kg/min), and the Ang-(1-7)/PAMAM-OH complex (2:1 molar ratio) were osmotically infused through micropumps (Alzet-Durect, Cupertino, CA, USA), as previously described, [15][16][17][18] 24 h before cast immobilization. After experimentation, the animals were euthanized under anesthesia and the gastrocnemius (GAST) muscles were dissected, removed, and rapidly frozen and stored at -80°C until processing.…”

“…[11][12][13][14] Related to this, a recent report described the effect of Ang-(1-7) as an anti-atrophic factor in skeletal muscle in Ang II-dependent and -independent models, such as in immobilization or sepsis. [15][16][17][18] Therefore, finding the mechanisms that potentiate the anti-atrophic actions of Ang-(1-7) is relevant in a therapeutic context. However, the instability of Ang-(1-7) restricts efficient oral or injected administration.…”

Angiotensin-(1-7) Prevents Skeletal Muscle Atrophy Induced by Transforming Growth Factor Type Beta (TGF-β) via Mas Receptor Activation

“…The alternative arm of RAS or non-classical RAS, is formed by ACE-2 that induces the synthesis of Ang-(1-7) peptide that acts via Mas receptor producing contrary effects than classical RAS [24,28]. In this context, our previous studies have shown that Ang-(1-7) prevents muscle atrophy induced by Ang-II, lipopolysaccharides, and disuse through the Mas receptor [29][30][31][32].…”

“…Wheat germ agglutinin (WGA) staining labels glycoproteins at the sarcolemma [29,31]. To stain the samples, freshly-frozen TA muscles were cryosectioned (8 µm) and placed on glass slides.…”