Circadian Clock Control of Muscle Stem Cells Through Temporal Coordination of Notch and Wnt Signaling

Abstract

The circadian clock regulates stem cell responses during tissue remodeling and repair. In skeletal muscle regeneration, successful regenerative myogenesis requires a temporally coordinated transition from Notch- to Wnt-driven signaling. However, the mechanisms governing this timing event remain poorly understood. Here, we show that circadian clock activity marks the cycling population of regeneration-activated myogenic progenitors that is induced in concert with Notch signaling. We identify key components of the Notch pathway as direct circadian clock targets and demonstrate that the clock coordinates Notch and Wnt signaling to drive myogenic progression. Genetic activation of the clock in satellite cells, as well as pharmacological clock stimulation, enhanced both proliferative expansion and subsequent differentiation of myogenic progenitors during regeneration. These effects were mediated by early activation of Notch signaling followed by increased Wnt pathway activity at later regenerative stages. Notably, both clock-dependent mechanisms remained functional in dystrophin-deficient mouse muscle and human myoblasts. Furthermore, clock-activating compounds enhanced regenerative myogenesis following acute injury and improved regeneration in dystrophic muscle. Collectively, these findings establish the circadian clock as a temporal regulator of regenerative signaling programs that orchestrate muscle repair with potential for targeted interventions.