Calcitonin receptor downregulation and exercise-conditioned blood enable systemic muscle stem cell proliferation.

Quiescent muscle stem cells (MuSCs) respond to exercise; however, the coordinated regulation of increased loading, exerkines, and quiescence signaling remains unclear. We found that increased loading reduces calcitonin receptor (CalcR) expression, and forced activation of protein kinase A (PKA), a downstream of CalcR signaling, suppresses MuSC proliferation. Although MuSC-specific Calcr knockout (C-cKO) alone is insufficient, exercised C-cKO mice exhibit significant MuSC proliferation independent of increased loading. Reinforcement of CalcR signaling, either through PKA induction or Yap1 depletion, suppresses MuSC proliferation. Load-independent MuSC proliferation is also suppressed by the deletion of gp130 in C-cKO mice. Serum from exercised mice recapitulates MuSC proliferation in all analyzed muscles of sedentary C-cKO mice, which is abrogated by anti-IL-6 antibodies, and we find cross-talk between CalcR and gp130 signaling via Yap1 phosphorylation. Together, our findings reveal an integrated mechanism by which increased loading, exerkine-gp130, and CalcR signaling converge to fine-tune MuSC activity during exercise.