Abstract: Adult muscle satellite cells (MuSCs) are mostly quiescent in uninjured muscles under normal homeostasis. Although several mechanisms underlying quiescence maintenance in adult MuSCs are already known, our understanding of the process remains incomplete. Here, we reveal that Keap1 regulates MuSC quiescence maintenance by suppressing the accumulation of Nrf2 protein. Inducible deletion of Keap1 activates MuSCs to different extent in a sex-specific manner via differential Nrf2 protein levels: in Keap1-null MuSCs from male mice, Nrf2 protein is at an intermediate level due to the action of a GSK3-dependent Nrf2 degradation system, which promotes mutant MuSCs to enter a GAlert-like state; in Keap1-null MuSCs from female mice, the loss of Keap1 together with estrogen-mediated GSK3 inactivation renders Nrf2 at its highest levels, which induces the expression of multiple metabolic genes resulting in metabolic reprogramming, spontaneous activation and gradual depletion of MuSCs. Consistently, interference of selected Nrf2-regulated metabolic genes impairs early activation of MuSCs. Our study reveals non-canonical roles of the Keap1/Nrf2 axis in regulating quiescence and early activation in MuSCs independently of its canonical roles in the antioxidant response.
Funding Source: Research grants 16101323, 16104724, C6018-19G, T13-605/18W, T13-602/21-N, C6001-21E from the Hong Kong Research Grant Council, the Innovation and Technology Commission ITCPD/17-9, and the Shenzhen Bay Laboratory S201101002
