Dlk1 regulates quiescence in calcitonin receptor-mutant muscle stem cells

Abstract

Muscle stem cells, also called muscle satellite cells (MuSCs), are responsible for skeletal muscle regeneration and are sustained in an undifferentiated and quiescent state under steady conditions. The calcitonin receptor (CalcR)-protein kinase A (PKA)-Yes-associated protein 1 (Yap1) axis is one pathway that maintains quiescence in MuSCs. Although CalcR signaling in MuSCs has been identified, the critical CalcR signaling targets are incompletely understood. Here, we show the relevance between the ectopic expression of delta-like non-canonical Notch ligand 1 (Dlk1) and the impaired quiescent state in CalcR-conditional knockout (cKO) MuSCs. Dlk1 expression was rarely detected in both quiescent and proliferating MuSCs in control mice, whereas Dlk1 expression was remarkably increased in CalcR-cKO MuSCs at both the mRNA and protein levels. It is noteworthy that all Ki67+ non-quiescent CalcR-cKO MuSCs express Dlk1, and non-quiescent CalcR-cKO MuSCs are enriched in the Dlk1+ fraction by cell sorting. Using mutant mice, we demonstrated that PKA-activation or Yap1-depletion suppressed Dlk1 expression in CalcR-cKO MuSCs, which suggests that the CalcR-PKA-Yap1 axis inhibits the expression of Dlk1 in quiescent MuSCs. Moreover, the loss of Dlk1 rescued the quiescent state in CalcR-cKO MuSCs, which indicates that the ectopic expression of Dlk1 disturbs quiescence in CalcR-cKO. Collectively, our results suggest that ectopically expressed Dlk1 is responsible for the impaired quiescence in CalcR-cKO MuSCs.

Integrative molecular roadmap for direct conversion of fibroblasts into myocytes and myogenic progenitor cells

“…These included Calcr, Musculin (Msc), Lgr5, Fos, Dmrt2, Fzd4, Gas1, Dek, Pitx3, Carm1, Sox8, Dbx1, and Plagl, many of which have been reported to regulate in vivo muscle regeneration and satellite cell activation (Fig. 6G) (30)(31)(32)(33)(34)(35)(36)(37)(38). Moreover, gene groups associated with critical pathways for satellite cell activation and proliferation including Notch, TGF-, Janus kinase (JAK)-signal transducer and activator of transcription (STAT), and WNT were significantly up-regulated in Pax7-nGFP + iMPCs (Fig.…”

Integrative molecular roadmap for direct conversion of fibroblasts into myocytes and myogenic progenitor cells

“…6G). These included Calcr, Musculin (Msc), Lgr5, Fos, Dmrt2, Fzd4, Gas1, Dek, Pitx3, Carm1, Sox8, Dbx1 and Plagl, many of which have been recently reported to regulate in vivo muscle regeneration and satellite cell activation [28][29][30][31][32][33][34][35][36] (Fig. 6G).…”

We need to talk—how muscle stem cells communicate

“…Binding of the peptide hormone Calcitonin to the CalcR causes its activation resulting in the activation of multiple signaling pathways through its interaction with different G-protein family members (Gs and Gq) involved in maintaining calcium homeostasis ( Masi and Brandi, 2007 ). In addition to regulating quiescence by signaling via the CalcR-protein kinase A (PKA)-Yes-associated protein 1 (Yap1) axis, CalcR is a molecular marker of MuSCs ( Wang et al, 2014 ; Yamaguchi et al, 2015 ; Zhang et al, 2019 ; Zhang L. et al, 2021 ). MuSCs are retained in a quiescent state by the Notch-ColV-CalcR signaling pathway ( Baghdadi et al, 2018 ).…”