# Transient hypoxia followed by progressive reoxygenation is required for muscle repair

## TL;DR

Muscle repair requires a cycle of low oxygen followed by gradual reoxygenation to properly activate muscle stem cells and promote healing.

## Contribution

The study reveals that progressive reoxygenation after transient hypoxia is essential for muscle repair via regulation of REV-ERBα.

## Key findings

- Prolonged hypoxia impairs muscle repair by reducing muscle stem cell differentiation and fusion.
- Sustained hypoxia increases RevErbα expression, altering late myogenic stages and promoting self-renewal.
- Pharmacological inhibition of REV-ERBα improves myogenesis under prolonged hypoxia.

## 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. Sustained hypoxia decreases the ability of MuSCs to differentiate and fuse independently of HIF-1α or HIF-2α. Prolonged hypoxia specifically affects the circadian clock by increasing Rev-erbα expression in MuSCs. Using pharmacological tools, we demonstrate that Rev-ERBα 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-ERBα.

Progressive muscle reoxygenation of injured muscle following transient hypoxia enhances the regenerative potential of muscle stem cells (MuSCs) and promotes efficient skeletal muscle repair through the regulation of REV-ERBα.

Skeletal muscle regeneration after injury is initiated in a low oxygen environment followed by gradual reoxygenation.Disrupting muscle reoxygenation by exposing mice to prolonged hypoxia impairs muscle repair by reducing the ability of MuSCs to differentiate and fuse.Sustained hypoxia alters the late stages of the myogenic program by increasing RevErbα expression in MuSCs, while simultaneously promoting their self-renewal through HIF-1α stabilization.

Skeletal muscle regeneration after injury is initiated in a low oxygen environment followed by gradual reoxygenation.

Disrupting muscle reoxygenation by exposing mice to prolonged hypoxia impairs muscle repair by reducing the ability of MuSCs to differentiate and fuse.

Sustained hypoxia alters the late stages of the myogenic program by increasing RevErbα expression in MuSCs, while simultaneously promoting their self-renewal through HIF-1α stabilization.

Progressive muscle reoxygenation of injured muscle following transient hypoxia enhances the regenerative potential of muscle stem cells (MuSCs) and promotes efficient skeletal muscle repair through the regulation of REV-ERBα.