Non-canonical roles of Keap1/Nrf2 in regulating quiescence and early activation in adult muscle stem cells

Adult muscle satellite cells (MuSCs) are mostly quiescent in uninjured muscles under normal homeostasis. Although several mechanisms underlying quiescence maintenance are known, our understanding of the process remains incomplete. Here, we show that Keap1 regulates MuSC quiescence maintenance by promoting Nrf2 protein degradation. 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 GSK3β-dependent Nrf2 degradation system, which promotes mutant MuSCs to enter a G_Alert-like state; in Keap1-null MuSCs from female mice, the loss of Keap1 together with estrogen-mediated GSK3β inactivation renders Nrf2 at its highest level, 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. Thus, Keap1/Nrf2 regulates quiescence maintenance and early activation of MuSCs independently of its canonical roles in the antioxidant response.