The Nuclear Receptor and Clock Repressor Rev-erbα Suppresses Myogenesis

Abstract

Rev-erbα is a ligand-dependent nuclear receptor and a key repressor of the molecular clock transcription network. Accumulating evidence indicate that the circadian clock machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair and mass maintenance. The physiological function of Rev-erbα in myogenic regulation remains largely unknown. Here we show that Rev-erbα exerts cell-autonomous inhibitory effects on proliferation and differentiation of myogenic precursor cells, and these actions concertedly inhibit muscle regeneration in vivo. Mechanistic studies reveal Rev-erbα direct transcriptional control of two major myogenic mechanisms, proliferative pathway and the Wnt signaling cascade. Consistent with this finding, primary myoblasts lacking Rev-erbα display significantly enhanced proliferative growth and myogenic progression. Furthermore, pharmacological activation of Rev-erbα activity attenuates, whereas its inhibition by an antagonist promotes these processes. Notably, upon muscle injury, the loss-of-function of Rev-erbα in vivo augmented satellite cell proliferative expansion and regenerative progression during regeneration. Collectively, our study identifies Rev-erbα as a novel inhibitory regulator of myogenic progenitor cell properties that suppresses postnatal myogenesis. Pharmacological interventions to dampen Rev-erbα activity may have potential utilities to enhance regenerative capacity in muscle diseases.

Chrono-Nutrition Has Potential in Preventing Age-Related Muscle Loss and Dysfunction

“…Freeze-or cardiotoxin-induced muscle regeneration was suppressed by the depletion of Bmal1 (Chatterjee et al, 2015). Recently, there has been evidence for the potential of Reverbα in preventing myogenesis through augmented satellite cell expansion and myogenic progression (Chatterjee et al, 2019).…”

Per1/Per2-Igf2 axis-mediated circadian regulation of myogenic differentiation

“…Bmal1 promotes satellite cell proliferation and differentiation, and is required for muscle regeneration 11,12 , Rev-erbα acts as an inhibitor of these processes 13 . Third, Clock/Bmal1 binds the E-box in the core enhancer of MyoD in a circadian manner; MyoD then binds the Bmal1 enhancer and increases the amplitude of Bmal1 expression, forming a feed-forward loop in myogenesis 14,15 .…”

“…First, more than 2,000 genes, including the master myogenic regulators MyoD and Myogenin (Myog), show circadian oscillation in abundance (Harfmann et al, 2015;McCarthy et al, 2007;Miller et al, 2007;Pizarro et al, 2013). Second, whereas Bmal1 promotes satellite cell proliferation and differentiation, and is required for muscle regeneration (Chatterjee et al, 2013;Chatterjee et al, 2015), Rev-erbα acts as an inhibitor of these processes (Chatterjee et al, 2019).…”

Metabolic‐sensing of the skeletal muscle clock coordinates fuel oxidation

“…Bmal1 and its obligate partner CLOCK are required for maintaining muscle contractile function and structural integrity 17 . Our previous studies reveal that Bmal1 is a key regulator of myocyte development in postnatal muscle growth and remodeling, 15,18 and in contrast, its transcriptional repressor Rev‐erbα suppresses myogenesis 19 . As a remarkable ~35% of rhythmic transcripts in skeletal muscl ebelongs to metabolic processes and metabolites in muscle display daily oscillations, circadian clock control is pervasive in muscle metabolism.…”