CCAAT/enhancer‐binding protein beta (C/EBPβ) promotes muscle satellite cell quiescence. (A) In resting muscle, satellite cells are quiescent and express both PAX7 and C/EBPβ. C/EBPβ promotes the expression of several quiescence‐associated genes including Cav1. (B) Muscle injury drives activation and proliferation of precursors with a concomitant reduction in C/EBPβ expression. (C) Low C/EBPβ expression promotes differentiation and muscle repair. (D) Cells that escape differentiation, self‐renew and return to quiescence are C/EBPβ+.
Abstract
Regeneration of skeletal muscle depends on resident muscle stem cells called satellite cells that in healthy, uninjured muscle remain quiescent (noncycling). After activation and expansion of satellite cells postinjury, satellite cell numbers return to uninjured levels and return to mitotic quiescence. Here, we show that the transcription factor CCAAT/enhancer‐binding protein beta (C/EBPβ) is required to maintain quiescence of satellite cells in uninjured muscle. We show that C/EBPβ is expressed in quiescent satellite cells in vivo and upregulated in noncycling myoblasts in vitro. Loss of C/EBPβ in satellite cells promotes their premature exit from quiescence resulting in spontaneous activation and differentiation of the stem cell pool. Forced expression of C/EBPβ in myoblasts inhibits proliferation by upregulation of 28 quiescence‐associated genes. Furthermore, we find that caveolin‐1 is a direct transcriptional target of C/EBPβ and is required for cell cycle exit in muscle satellite cells expressing C/EBPβ. The induction of mitotic quiescence is considered necessary for the long‐term maintenance of adult stem cell populations with dysregulation driving increased differentiation of progenitors and depletion of the stem cell pool. Our findings place C/EBPβ as an important transcriptional regulator of muscle satellite cell quiescence.