Physical training reduces cell senescence and associated insulin resistance in skeletal muscle.

BACKGROUND: Cell senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood. OBJECTIVES: This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention. METHODS: Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, in vitro experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling. RESULTS: Individuals with obesity showed significantly elevated CS markers, along with reduced expression of GLUT4 and PAX7, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit. CONCLUSIONS: These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.