Transient hypoxia followed by progressive reoxygenation is required for efficient skeletal muscle repair through Rev-ERBalpha modulation

Abstract

Muscle stem cells (MuSCs) are essential for skeletal muscle repair. Following injury, MuSCs reside in low oxygen environments until muscle fibers and vascularization are restablished. The dynamics of oxygen levels during the regenerative process and its impact on muscle repair has been underappreciated. We confirm that muscle repair is initiated in a low oxygen environment followed by gradual reoxygenation. Strikingly, when muscle reoxygenation is limited by keeping mice under systemic hypoxia, muscle repair is impaired and leads to the formation of hypotrophic myofibers. In vivo, sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1. Prolonged hypoxia specifically affects the circadian clock by increasing Rev-erb expression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERB negatively regulates myogenesis by reducing late myogenic cell fusion under prolonged hypoxia. Our results underscore the critical role of progressive muscle reoxygenation after transient hypoxia in coordinating proper myogenesis through Rev-ERB.