Cellular Senescence in Skeletal Muscle: Age, Sarcopenia, Therapy

Abstract Progressive age-related decline in skeletal muscle mass, strength, and function results in muscle fiber loss and atrophy, with associated replacement by adipose and fibrous tissue, or sarcopenia. Muscles are liable to multiple forms of molecular and cellular damage, including impaired regenerative capacity and protein turnover, mitochondrial dysfunction, and cellular senescence, which manifests as cell cycle arrest. With age, these cells accumulate and acquire distinctive properties characterized by chromatin changes and the emergence of a specific secretory senescence-associated phenotype (SAS phenotype), which exerts local and/or systemic negative effects on tissues. The aim of this review is to present the landscape of cellular senescence in skeletal muscle, based on the evidence for their role in age-related changes in muscle mass, strength, function, and clinical consequences of this phenomenon, as well as to outline key directions in developing novel anti-senescence therapies for sarcopenia. Data search was carried out in Google Scholar, Medline, PubMed, Scopus, Web of Science, and Cochrane Library electronic scientific databases using keywords and their combinations, with the AMSTAR 2 software. Publication selection (82 included out of 430) was performed randomly, followed by independent assessment of their methodological quality. The crucial role of cellular senescence in shaping the SAS phenotype in the age-related pathophysiology of skeletal muscles has been proven. These phenomena alter muscle tissue homeostasis and contribute to the onset and progression of sarcopenia. Targeting senescent cells and their secretory profiles may facilitate the development of complex strategies, including the use of senolytics and senomorphics, to improve the quality of life in aging human populations. On the other hand, there are currently insufficient data on the vulnerability to aging of terminally differentiated skeletal muscle fibers and resident mononuclear cells in the interstitial microenvironment. A range of opinions is discussied on how this phenomenon contributes to the onset and progression of age-related skeletal muscle loss and dysfunction, as well as the initiation of sarcopenia. Scientific advancements in this field will enable the identification of novel therapeutic approaches to optimizing muscle health in old age.