The influence of age on cellular senescence in injured versus healthy muscle and its implications on rotator cuff injuries

BACKGROUND: Advanced age increases the prevalence of rotator cuff tears and affects the success of repair surgeries. Cellular senescence is proposed as a key mechanism behind these age-related differences, likely due to contribution of the senescence-associated secretory phenotype. This state is linked to various age-related diseases, including rotator cuff injuries. MATERIALS AND METHODS: Rotator cuff muscle samples were obtained from young and aged patients who underwent surgery. Samples were processed for single-cell RNA sequencing to analyze cellular differences. Cells were isolated and sequenced to identify different cell populations and their gene expression profiles. RESULTS: Six major cell populations were identified in rotator cuff muscle tissue, including fibroadipogenic progenitor cells (FAPs), satellite cells, endothelial cells, pericytes, macrophages, and T cells. Aged FAPs showed higher expression of senescence markers and genes associated with fibrosis and inflammation. Younger FAPs had higher levels of extracellular matrix remodeling genes. Specifically, ATF3-a senescence marker-was found to be elevated in aged FAPs. In silico analysis highlighted a potential role of ATF3 in regulating FAP differentiation. CONCLUSIONS: Markers of cellular senescence are significantly elevated in older human rotator cuff tissue samples compared with young rotator cuff. Of specific interest is ATF3, a gene that has been previously implicated in regulating adipogenesis, which demonstrates a trend to function in a protective capacity against the formation of fibrosis in computational analysis of our data.