Circadian Clock Coordination of the Notch-to-Wnt Signaling Switch Promotes Regenerative Myogenesis
- 1Beckman Research Institute of City of Hope
Abstract
Regenerative deficits of muscle stem cells (MuSCs) contribute to progressive muscle loss in muscular dystrophy. Successful regenerative repair requires a Notch to Wnt switch to allow MuSC expansion and myogenic differentiation, yet the underlying mechanisms remain poorly understood. Leveraging complementary genetic and pharmacological approaches, here we identify the circadian clock as a key regulator of the Notch to Wnt signaling transition to promote regeneration with therapeutic potential for dystrophic disease. Circadian clock activity marks cycling myogenic progenitors during muscle regeneration, and clock induction occurs in concert with Notch activation. We identify that key components of the Notch pathway are direct transcriptional targets of the clock that were induced by clock activation. Mechanistically, clock coordination of Notch and Wnt signaling promoted MuSC proliferative expansion while facilitating myogenic progression during regeneration. Importantly, this clock-regulated mechanism was preserved in dystrophin-deficient mouse and human myoblasts, and clock-activating compounds enhanced regenerative myogenesis in dystrophic muscle. Collectively, our findings uncover a circadian clock-controlled mechanism that orchestrates regenerative signaling transition with potential for therapeutic targeting to restore regenerative capacity in dystrophic disease.
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BibTeX
@misc{kiperman2026circadian,
title = {{Circadian Clock Coordination of the Notch-to-Wnt Signaling Switch Promotes Regenerative Myogenesis}},
author = {T. Kiperman and X. Xiong and J. Pangemanan and D. A. Horne and V. K. Yechoor and K. Ma},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.31.763285},
url = {https://www.biorxiv.org/content/10.64898/2026.10.31.763285v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Circadian Clock Coordination of the Notch-to-Wnt Signaling Switch Promotes Regenerative Myogenesis
AU - T. Kiperman
AU - X. Xiong
AU - J. Pangemanan
AU - D. A. Horne
AU - V. K. Yechoor
AU - K. Ma
PY - 2026
DA - 2026/10/31
PB - bioRxiv
DO - 10.64898/2026.10.31.763285
UR - https://www.biorxiv.org/content/10.64898/2026.10.31.763285v1
AB - Regenerative deficits of muscle stem cells (MuSCs) contribute to progressive muscle loss in muscular dystrophy. Successful regenerative repair requires a Notch to Wnt switch to allow MuSC expansion and myogenic differentiation, yet the underlying mechanisms remain poorly understood. Leveraging complementary genetic and pharmacological approaches, here we identify the circadian clock as a key regulator of the Notch to Wnt signaling transition to promote regeneration with therapeutic potential for dystrophic disease. Circadian clock activity marks cycling myogenic progenitors during muscle regeneration, and clock induction occurs in concert with Notch activation. We identify that key components of the Notch pathway are direct transcriptional targets of the clock that were induced by clock activation. Mechanistically, clock coordination of Notch and Wnt signaling promoted MuSC proliferative expansion while facilitating myogenic progression during regeneration. Importantly, this clock-regulated mechanism was preserved in dystrophin-deficient mouse and human myoblasts, and clock-activating compounds enhanced regenerative myogenesis in dystrophic muscle. Collectively, our findings uncover a circadian clock-controlled mechanism that orchestrates regenerative signaling transition with potential for therapeutic targeting to restore regenerative capacity in dystrophic disease.
ER -