The angiotensin-(1–7)/Mas axis reduces myonuclear apoptosis during recovery from angiotensin II-induced skeletal muscle atrophy in mice

Abstract

Angiotensin-(1-7) [Ang (1-7)] is a peptide belonging to the non-classical renin-angiotensin system (RAS). Ang (1-7), through its receptor Mas, has an opposite action to angiotensin II (Ang II), the typical peptide of the classical RAS axis. Ang II produces skeletal muscle atrophy, a pathological condition characterised by the loss of strength and muscle mass. A feature of muscle atrophy is the decrease of the myofibrillar proteins produced by the activation of the ubiquitin-proteasome pathway (UPP), evidenced by the increase in the expression of two muscle-specific ubiquitin ligases: atrogin-1 and MuRF-1. In addition, it has been described that Ang II also induces myonuclear apoptosis during muscle atrophy. We assessed the effects of Ang (1-7) and Mas participation on myonuclear apoptosis during skeletal muscle atrophy induced by Ang II. Our results show that Ang (1-7), through Mas, prevents the effects induced by Ang II in the diaphragm muscles and decreases several events associated with apoptosis in the diaphragm (increased apoptotic nuclei, increased expression of caspase-8 and caspase-9, increased caspase-3 activity and increased Bax/Bcl-2 ratio). Concomitantly, Ang (1-7) also attenuates the decrease in fibre diameter and muscle strength, and prevents the increase in atrogin-1 and MuRF-1 during the muscle wasting induced by Ang II. Interestingly, these effects of Ang (1-7) are dependent on the Mas receptor. Thus, we demonstrated for the first time that Ang (1-7) prevents myonuclear apoptosis during the recovery of skeletal muscle atrophy induced by Ang II.

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.…”

Muscle memory and a new cellular model for muscle atrophy and hypertrophy

“…Adhihetty et al, 2007;Allen et al, 1997;Alway et al, 2003b;Meneses et al, 2014;Tews et al, 1997;Yoshimura and Harii, 1999). However, with such a technique it is difficult to distinguish between nuclei of different cell types, in particular satellite cells, which are located under the basal lamina of the muscle fibres.…”

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].…”