“Skeletal muscle displays an age-associated decline in motor function and muscle mass.”
BUFFALO, NY — June 23, 2026 — A new research paper was published in Volume 18 of Aging on May 28, 2026, titled “p38MAP kinase regulates senescence in human iPS-derived myocytes.”
The study was led by first author Hiroki Sato and corresponding author Ryuichiro Sato from The University of Tokyo, along with corresponding author Makoto Shimizu from The University of Tokyo and Ochanomizu University.
As people age, skeletal muscle gradually loses strength, mass, and function, contributing to frailty, reduced mobility, and an increased risk of falls. Although cellular senescence is widely recognized as a major driver of aging, the mechanisms that promote aging within mature muscle fibers remain poorly understood. In this study, researchers developed a human cell-based model to investigate how senescence develops in skeletal muscle cells and identified a signaling pathway that appears to play a central role in the process.
The research team used human induced pluripotent stem cell (iPSC)-derived myocytes, specialized muscle cells generated from stem cells. To mimic age-related cellular damage, the investigators exposed the cells to low-dose X-ray irradiation, which induced DNA damage without causing extensive cell death.
The treated muscle cells developed several characteristics commonly associated with aging. They exhibited muscle fiber atrophy, reduced contractile activity, and increased expression of p21, a well-established marker of cellular senescence. The researchers also observed elevated production of senescence-associated secretory phenotype (SASP) factors, inflammatory and extracellular signaling molecules that are commonly released by senescent cells.
To better understand the molecular changes involved, the investigators performed proteomic, transcriptomic, and functional analyses. These studies revealed activation of p38 mitogen-activated protein kinase (p38MAPK), a signaling pathway previously linked to cellular stress responses and aging in other tissues.
Further experiments demonstrated that inhibiting p38MAPK partially attenuated several senescence-associated features in the muscle cells. Treatment with p38MAPK inhibitors reduced muscle fiber atrophy, improved contractile function, and suppressed the expression of several senescence-associated factors. Conversely, activating p38MAPK promoted aging-like changes in the cells, further supporting its role in regulating muscle cell senescence.
The study also identified activation of an integrin–FAK/SRC–p38MAPK signaling axis following DNA damage. According to the authors, this pathway may help explain how cellular stress is translated into long-term functional decline in skeletal muscle.
Importantly, the findings were supported by analyses of human muscle aging datasets, which showed increased activity of MAPK signaling, focal adhesion pathways, and cytokine-related signaling in older skeletal muscle tissue.
“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.”
According to the authors, the study provides a valuable experimental platform for investigating the biology of muscle aging and evaluating potential anti-aging interventions. By identifying p38MAPK as a key regulator of senescence in human muscle cells, the findings also suggest that targeting this pathway could help preserve muscle function during aging.
Overall, the study offers new insight into the molecular mechanisms that drive skeletal muscle aging. The results highlight p38MAPK as a central mediator of senescence-related changes in human muscle cells and provide a promising framework for future research aimed at combating age-related muscle decline.
Paper DOI: https://doi.org/10.18632/aging.206385
Corresponding authors: Ryuichiro Sato – [email protected], Makoto Shimizu – [email protected]
Keywords: senescence, aging, skeletal muscle, iPS cell, p38MAP kinase, DNA damage
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