Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass

Abstract

The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and thermogenesis. We have previously demonstrated that Rev-erb-α is also an important regulator of skeletal muscle mitochondrial biogenesis and function, and autophagy. As such, Rev-erb-α over-expression in skeletal muscle or its pharmacological activation improved mitochondrial respiration and enhanced exercise capacity. Here, in gain- and loss-of function studies, we show that Rev-erb-α also controls muscle mass. Rev-erb-α-deficiency in skeletal muscle leads to increased expression of the atrophy-related genes (atrogenes), associated with reduced muscle mass and decreased fiber size. By contrast, in vivo and in vitro Rev-erb-α over-expression results in reduced atrogenes expression and increased fiber size. Finally, Rev-erb-α pharmacological activation blocks dexamethasone-induced upregulation of atrogenes and muscle atrophy. This study identifies Rev-erb-α as a promising pharmacological target to preserve muscle mass.

SR9009 has REV-ERB–independent effects on cell proliferation and metabolism

“…mESCs are similar to cancer cells in terms of their high proliferative capacity. Consistent with a previous report studying cancer cell lines (11), we found that treatment with SR9009 for 2 d at a concentration (10 μM) used in many published studies (24,28,32,34,(42)(43)(44) reduced the viability of immortalized mouse and human cell lines, including some cancer cells (SI Appendix, Fig. S2A) but not fibroblasts (SI Appendix, Fig.…”

“…Like other NRs, REV-ERBs can be regulated by ligands, including naturally occurring heme (22,23), which modulate their repressive activity. Attempts to pharmacologically target REV-ERBs by the use of putatively specific synthetic agonists, particularly SR9009 (24), have suggested a wide range of beneficial effects in healthy as well as diseased animal models and cell systems (11,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). The beneficial effects of SR9009 on weight and exercise in mice (24,27) have led to an interest in the use of the compound by humans, with online advertisements selling SR9009 highlighting REV-ERBs as the molecular target (e.g., https://www.simplyanabolics.com/sarms/sr9009-stenabolic/).…”

Rev-erbα heterozygosity produces a dose-dependent phenotypic advantage in mice

“…Rev-erb null mice stimulated catabolic genes exclusively (Fig 3c) with no effect on anabolic expression ( Fig 3D), in agreement with previous findings [19]. Further investigation revealed an increase in FOXO3A protein expression ( Fig 3E) and STAT3 phosphorylation in the SkM of the Nr1d1 -/mice ( Fig 3F).…”

“…Heterozygous mice also showed an enhanced regenerative response to injury compared to wildtype mice [16]. Rev-erb null mice are known to display elevated expression of mediators of muscle atrophy, impaired muscle function, and a progressive decline in myofiber size due to enhanced protein catabolism [19]. In order to decipher the metabolic underpinnings of this gene dose-effect we comprehensively characterized the metabolic phenotype of Nr1d1 +/mice.…”

Rev-erb-α : une cible thérapeutique contre la perte de masse musculaire ?

“…Nous travaillons sur le récepteur nucléaire Rev-erb-α, une protéine de l'horloge biologique, dont l'activité est modulable par des ligands synthétiques [3]. Notre équipe a montré que l'administration de l'agoniste SR9009 de Rev-erb améliore la performance musculaire des souris en augmentant la biogenèse mitochondriale musculaire [4], et prévient l'atrophie musculaire induite par la dexaméthasone en inhibant l'activation des gènes proatrophiques [5]. Toutefois, le rôle de Rev-erb-α dans le stress réticu-laire, réponse cellulaire pouvant conduire à l'apoptose, n'a jamais été exploré.…”