The life and times of cellular senescence in skeletal muscle: friend or foe for homeostasis and adaptation?

A gradual decline in skeletal muscle mass and function is closely tied to increased mortality and disease risk during organismal aging. Exercise training is the most effective way to enhance muscle health, but the adaptive response to exercise as well as muscle repair potential is blunted in older individuals. Numerous mechanisms contribute to the loss of muscle mass and plasticity as aging progresses. An emerging body of recent evidence implicates an accumulation of senescent ("zombie") cells in muscle as a contributing factor to the aging phenotype. Senescent cells cannot divide but can release inflammatory factors and create an unfavorable environment for homeostasis and adaptation. On balance, some evidence indicates that cells with senescent characteristics can be beneficial for the muscle adaptive process, specifically at younger ages. Emerging evidence also suggests that multinuclear muscle fibers could become senescent. In this review, we summarize current literature on the prevalence of senescent cells in skeletal muscle and highlight the consequences of senescent cell removal on muscle mass, function, and adaptability. We examine key limitations in the field of senescence specifically in skeletal muscle and identify areas of research that require future investigation. There is evidence to suggest that senescent "zombie" cells may or may not accrue in aging skeletal muscle. When muscle is perturbed regardless of age, senescent-like cells do appear, and the benefits of removing them could be age-dependent. More work is needed to determine the magnitude of accumulation and source of senescent cells in muscle. Regardless, pharmacological senolytic treatment of aged muscle is beneficial for adaptation.