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

Abstract

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.