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.
Authors
- Masaaki Murakami (ORCID: https://orcid.org/0000-0002-2294-194X)
- Ayasa Nakamura
- Takashi Yamada (ORCID: https://orcid.org/0000-0003-1797-3880)
- Takayuki Kaji
- Takayuki Akimoto (ORCID: https://orcid.org/0000-0002-8874-7779)
- Atsushi Kubo (ORCID: https://orcid.org/0000-0002-6457-5386)
- Akiyoshi Uezumi (ORCID: https://orcid.org/0000-0003-4294-0116)
- So‐ichiro Fukada (ORCID: https://orcid.org/0000-0003-4051-5108)
- Daisuke Kamimura (ORCID: https://orcid.org/0000-0003-1022-4430)
- Kanako Iwamori
- Lidan Zhang (ORCID: https://orcid.org/0009-0008-0982-4934)
- Yilin Liu (ORCID: https://orcid.org/0000-0002-6661-6313)
- Jiayao Xu (ORCID: https://orcid.org/0009-0000-4145-8227)
- Nagomu Maesawa (ORCID: https://orcid.org/0009-0002-7244-4893)
Institutions
- Hiroshima University (JP)
- Kyushu University (JP)
- Waseda University (JP)
- Hokkaido University (JP)
- National Institutes for Quantum Science and Technology (JP)
- National Institute for Physiological Sciences (JP)
- Chongqing Medical University (CN)
- Osaka University of Pharmaceutical Sciences (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-26
- DOI
- https://doi.org/10.1038/s41467-025-65684-1
- Citations
- 1
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Suzuken Memorial Foundation
- Japan Agency for Medical Research and Development
- National Natural Science Foundation of China
- Chongqing Medical University
- Centre Scientifique et Technique du Bâtiment