Research Paper|Volume 18|pp 622—638

p38MAP kinase regulates senescence in human iPS-derived myocytes

Hiroki Sato¹, Momoka Arakane², Yuto Mizuno¹, Takashi Sasaki¹, Hidetoshi Sakurai³, Masamichi Kamihira⁴, Atsushi Enomoto⁵, Kazuaki Takafuji⁶, Junichiro Takaya⁶, Toshihide Suzuki⁶, Yu Takahashi⁷, Yoshio Yamauchi^1,⁷, Ryuichiro Sato¹, Makoto Shimizu^1,^2,⁸

¹Nutri-Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
²Laboratory of Nutrition and Life Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo 112-8610, Japan
³Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan
⁴Department of Chemical Engineering, Faculty of Engineering, Kyushu University, Fukuoka 819-0395, Japan
⁵Laboratory of Molecular Radiology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo 113-0033, Japan
⁶Research Institute, Suntory Global Innovation Center, Ltd., Kyoto 619-0284, Japan
⁷Laboratory of Food Biochemistry, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
⁸Institute for Human Life Innovation, Ochanomizu University, Tokyo 112-8610, Japan

Received: August 11, 2025Accepted: May 6, 2026Published: May 28, 2026

https://doi.org/10.18632/aging.206385

Copyright: © 2026 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Skeletal muscle displays an age-associated decline in motor function and muscle mass. However, the precise mechanisms underlying skeletal muscle aging, particularly within muscle fibers, remain poorly understood. Here, we demonstrate that DNA damage induced by X-ray irradiation triggers a senescence-like phenotype in human iPS cell (iPSC)-derived myocytes. This irradiation leads to muscle fiber atrophy and reduced contractile activity, accompanied by elevated expression of the aging marker p21. Omics analyses revealed that DNA damage activates p38 mitogen-activated protein kinase (p38MAPK). Inhibition of p38MAPK mitigated the senescence-like phenotype. These results suggest that activation of p38MAPK plays a role in regulating skeletal muscle senescence and that DNA damage-induced senescence in iPSC-derived myocytes represents a viable model for studying human skeletal muscle senescence.