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<p>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 <i>Calcr</i> 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 <i>gp130</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月26日

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  • Lidan Zhang,
  • Takayuki Kaji,
  • Ayasa Nakamura,
  • Nagomu Maesawa,
  • Kanako Iwamori,
  • Jiayao Xu,
  • Yilin Liu,
  • Akiyoshi Uezumi,
  • Daisuke Kamimura,
  • Masaaki Murakami,
  • Atsushi Kubo,
  • Takashi Yamada,
  • Takayuki Akimoto,
  • So-ichiro Fukada

摘要

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.