Creb3l1 Overexpression Improves Flexor Tendon Repair in Aged Rats

Aging increases tendon injury incidence and poor repair outcomes, but age-related differences in tendon mechanical properties and underlying mechanisms remain unclear. We first analyzed data from the Global Burden of Disease (GBD) database to characterize the associations between aging and population-level changes in tendon injury burden. We found the age-standardized incidence rate (ASIR) of tendon injuries caused by mechanical force decreased with advancing age, whereas the age-standardized prevalence rate (ASPR) increased with age, and the years lived with disability (YLDs) due to tendon injuries also showed an increasing trend with age. Guided by these epidemiological observations, we further performed ex vivo biomechanical assessments using aged rat flexor digitorum longus (FDL) tendon injury models to validate age-related mechanical deterioration at the tissue level, revealing significantly compromised mechanical properties in aged female rat tendons. To uncover the molecular drivers underlying such age-dependent mechanical degeneration, we conducted single-cell RNA sequencing of tendon tissues and identified downregulated expression of Col1a1 and Sparc in aged tendons. According to the JASPAR website prediction, the transcription factor Creb3l1 could bind to the promoter regions of both Col1a1 and Sparc genes simultaneously, and its overexpression promoted their expression. Finally, in vivo Creb3l1 overexpression upregulated the levels of Col1a1 and Sparc proteins and improved the gliding function, healing strength, and elastic modulus of aged tendons, especially in aged male rats. Collectively, this study links population-based epidemiological evidence with preclinical functional and mechanistic validation, providing insights for risk prediction and novel therapeutic targets for age-related tendon injuries.