Abstract
ABSTRACTImmobilization 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 atrophy in vivo using 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.
Highlights
IntroductionDisuse muscle atrophy is induced by low mechanical load (e.g. cast immobilization) (Bodine, 2013)
Disuse muscle atrophy is induced by low mechanical load (Bodine, 2013)
Ang-(1-7) prevents the decreased muscle strength of disuse atrophy through the Mas receptor Decreased muscle strength is a main feature of cast-immobilization skeletal muscle atrophy
Summary
Disuse muscle atrophy is induced by low mechanical load (e.g. cast immobilization) (Bodine, 2013). Morphological changes of disuse include decreased muscle mass, cross-sectional muscle fiber area, and strength (Bodine, 2013). Muscle mass maintenance depends on protein synthesis and degradation equilibrium, which are unbalanced during muscle wasting (Brooks and Myburgh, 2014). Activity of the IGF-1/Akt protein-synthesis pathway is decreased (Latres et al, 2005; Clemmons, 2009; Frost and Lang, 2007). The atrophy F-box protein (MAFbx; known as atrogin-1) and RING-finger protein-1 (MuRF-1), musclespecific E3 ligases, are upregulated in various skeletal muscle wasting models (Foletta et al, 2011) and are gene targets of Forkhead box, class O (FoxO) transcription factors (Sandri, 2008)
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