Age-related loss of skeletal muscle strength, mass, and function is a major contributor to frailty, reduced mobility, and increased fall risk in older adults. While cellular senescence is recognized as a fundamental driver of aging, the mechanisms underlying senescence in mature muscle cells have remained unclear. In this study, researchers developed a human cell-based model to investigate skeletal muscle aging and identified the p38MAPK signaling pathway as a key regulator of the process.

The team utilized human induced pluripotent stem cell (iPSC)-derived myocytes and induced age-like cellular damage through low-dose X-ray irradiation, which caused DNA damage without extensive cell death. Following treatment, the muscle cells displayed several hallmarks of aging, including muscle fiber atrophy, reduced contractile capacity, increased expression of the senescence marker p21, and elevated production of senescence-associated secretory phenotype (SASP) factors.

Through comprehensive proteomic, transcriptomic, and functional analyses, the researchers identified activation of the p38 mitogen-activated protein kinase (p38MAPK) pathway, a well-known mediator of cellular stress responses. Inhibition of p38MAPK partially reversed several aging-related changes, reducing muscle fiber atrophy, improving contractile function, and suppressing senescence-associated signaling. In contrast, activation of p38MAPK accelerated aging-like characteristics in the muscle cells.

Further investigation revealed that DNA damage activated an integrin–FAK/SRC–p38MAPK signaling cascade, providing insight into how cellular stress may drive long-term deterioration of skeletal muscle function. Analyses of human muscle aging datasets supported these findings, demonstrating increased activity of MAPK signaling, focal adhesion pathways, and cytokine-related signaling in older muscle tissue.

The findings suggest that p38MAPK plays a central role in regulating skeletal muscle senescence and highlight DNA damage-induced senescence in iPSC-derived myocytes as a valuable model for studying human muscle aging. By identifying p38MAPK as a potential therapeutic target, the study offers new opportunities for developing interventions aimed at preserving muscle health and reducing age-related functional decline.

Source: https://www.aging-us.com/news-room/researchers-identify-key-signaling-pathway-driving-muscle-cell-aging