Pathological calcium overload impairs skeletal muscle regeneration through sustained NFAT-dependent proliferative signaling
6 affiliations
- 1Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea
- 2School of Biological Science and Technology, Chonnam National University, Gwangju, Republic of Korea
- 3Department of Orthopedic Surgery, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
- 4Department of Pathology, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon, Republic of Korea
- 5Department of Biological Sciences, College of Natural Sciences, Keimyung University, Daegu, Republic of Korea
- 6Department of Bio and Environmental Technology, Seoul Women’s University, Seoul, Republic of Korea
Abstract
Skeletal muscle regeneration requires coordinated myoblast proliferation and differentiation. Calcium dysregulation is commonly observed in aging and disease-associated muscle weakness; however, its impact on myogenic progression remains unclear. In this study, we investigated the mechanism by which intracellular calcium overload impairs myogenic differentiation and muscle regeneration. Transcriptomic analysis of aged human muscle revealed coordinated activation of calcium signaling and proliferation pathways. In vitro calcium exposure increased myoblast proliferation under differentiation conditions while suppressing myogenic markers. RNA sequencing identified upregulation of proliferative programs with concurrent suppression of myogenic genes and enrichment of calcium–NFAT signaling. Mechanistically, calcium promoted NFATc1 nuclear translocation and upregulated Ccnd1 expression. Consistent with these in vitro findings, both ovariectomized mice (systemic calcium dysregulation) and human calcific tendinitis tissues (localized calcium overload) exhibited NFAT-associated proliferative signatures with suppressed myogenic markers. The selective NFAT inhibitor VIVIT prevented calcium-induced NFATc1 nuclear accumulation and restored myotube formation in vitro, while promoting myofiber maturation in an in vivo injury model. These findings implicate chronic calcium–NFAT signaling as a mechanism linking calcium dysregulation to impaired muscle regeneration.
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BibTeX
@article{lee2026pathological,
title = {{Pathological calcium overload impairs skeletal muscle regeneration through sustained NFAT-dependent proliferative signaling}},
author = {Sangsoo Lee and Namjoon Cho and Seokwoo Jo and Jong-Hun Ji and Jong Ok Kim and Chungoo Park and Sunkyung Choi and Eun-Mi Kim and Kee K. Kim},
journal = {Experimental \& Molecular Medicine},
year = {2026},
month = oct,
doi = {10.1038/s12276-026-01856-3},
url = {https://doi.org/10.1038/s12276-026-01856-3},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Pathological calcium overload impairs skeletal muscle regeneration through sustained NFAT-dependent proliferative signaling
AU - Sangsoo Lee
AU - Namjoon Cho
AU - Seokwoo Jo
AU - Jong-Hun Ji
AU - Jong Ok Kim
AU - Chungoo Park
AU - Sunkyung Choi
AU - Eun-Mi Kim
AU - Kee K. Kim
PY - 2026
DA - 2026/10/02
JO - Experimental & Molecular Medicine
DO - 10.1038/s12276-026-01856-3
UR - https://doi.org/10.1038/s12276-026-01856-3
AB - Skeletal muscle regeneration requires coordinated myoblast proliferation and differentiation. Calcium dysregulation is commonly observed in aging and disease-associated muscle weakness; however, its impact on myogenic progression remains unclear. In this study, we investigated the mechanism by which intracellular calcium overload impairs myogenic differentiation and muscle regeneration. Transcriptomic analysis of aged human muscle revealed coordinated activation of calcium signaling and proliferation pathways. In vitro calcium exposure increased myoblast proliferation under differentiation conditions while suppressing myogenic markers. RNA sequencing identified upregulation of proliferative programs with concurrent suppression of myogenic genes and enrichment of calcium–NFAT signaling. Mechanistically, calcium promoted NFATc1 nuclear translocation and upregulated Ccnd1 expression. Consistent with these in vitro findings, both ovariectomized mice (systemic calcium dysregulation) and human calcific tendinitis tissues (localized calcium overload) exhibited NFAT-associated proliferative signatures with suppressed myogenic markers. The selective NFAT inhibitor VIVIT prevented calcium-induced NFATc1 nuclear accumulation and restored myotube formation in vitro, while promoting myofiber maturation in an in vivo injury model. These findings implicate chronic calcium–NFAT signaling as a mechanism linking calcium dysregulation to impaired muscle regeneration.
SN - 1226-3613
SN - 2092-6413
ER -