Activation of tripartite motif-containing protein 16 improves cardiac function in aging mice by regulating Mfn2-dependent mitochondrial fusion through Sirt6

Aging increases susceptibility to various diseases, including cardiac injury. Which leads to cardiac dysfunction by increasing myocardial fibrosis and mitochondrial dynamics disorder. However, the molecular mechanisms in the aging heart have not been elucidated. The E3 Ligase TRIM16 (tripartite motif-containing protein 16) functions as a regulator to alleviate cardiac injury. SIRT6 has been shown to play a cardioprotective role by maintaining mitochondrial dynamics. Our study aimed to elucidate the molecular mechanisms of the TRIM16-Sirt6-Mfn2 signaling pathway in the aging heart. We used aged mice and performed intracardiac injections of AAV-TRIM16/SIRT6. The results demonstrated that TRIM16 improved cardiac function by increasing SIRT6 expression in the aging heart. Further in vitro studies were conducted using D-galactose-cultured h9c2 cells to explore the relationship between TRIM16/SIRT6 and mitochondrial dynamics. The findings showed that TRIM16/SIRT6 protected D-galactose-cultured h9c2 cells by promoting Mfn2-dependent mitochondrial fusion and enhancing mitochondrial respiratory capacity. In conclusion, our results confirm that TRIM16 activation improves cardiac function via the SIRT6/Mfn2 signaling pathway in the aging heart. This study provides evidence that TRIM16/SIRT6/Mfn2 signaling plays a novel protective role in the aging heart and offers a promising therapeutic strategy for age-related heart failure.