BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells

Pei Zhu, Noah X. Hamlish, Abhishek Vijay Thakkar, Adam W.T. Steffeck, Emily J. Rendleman, Nabiha H. Khan, Nathan J. Waldeck, Andrew W. DeVilbiss, Misty S. Martin-Sandoval, Thomas P. Mathews, Navdeep S. Chandel, Clara B. Peek*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The process of tissue regeneration occurs in a developmentally timed manner, yet the role of circadian timing is not understood. Here, we identify a role for the adult muscle stem cell (MuSC)-autonomous clock in the control of muscle regeneration following acute ischemic injury. We observed greater muscle repair capacity following injury during the active/wake period as compared with the inactive/rest period in mice, and loss of Bmal1 within MuSCs leads to impaired muscle regeneration. We demonstrate that Bmal1 loss in MuSCs leads to reduced activated MuSC number at day 3 postinjury, indicating a failure to properly expand the myogenic precursor pool. In cultured primary myoblasts, we observed that loss of Bmal1 impairs cell proliferation in hypoxia (a condition that occurs in the first 1–3 d following tissue injury in vivo), as well as subsequent myofiber differentiation. Loss of Bmal1 in both cultured myoblasts and in vivo activated MuSCs leads to reduced glycolysis and premature activation of prodifferentiation gene transcription and epigenetic remodeling. Finally, hypoxic cell proliferation and myofiber formation in Bmal1-deficient myoblasts are restored by increasing cytosolic NAD+. Together, we identify the MuSC clock as a pivotal regulator of oxygen-dependent myoblast cell fate and muscle repair through the control of the NAD+-driven response to injury.

Original languageEnglish (US)
Pages (from-to)149-166
Number of pages18
JournalGenes and Development
Volume36
Issue number3-4
DOIs
StatePublished - Feb 1 2022

Keywords

  • Circadian rhythm
  • Hypoxia
  • Muscle regeneration
  • Muscle stem cell]
  • NAD

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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