SIRT3-dependent enhancement of apelinergic signaling mediates the cardioprotective effects of late-life high-intensity interval training

BACKGROUND: Deficiency in apelinergic signaling (APJ/Apelin) has been shown to accelerate cardiac aging. Given our observation that high-intensity interval training (HIIT) upregulates APJ and Apelin in aged mouse hearts, this study aimed to investigate whether apelinergic signaling mediates the cardioprotective effects of exercise. METHODS: Naturally aged (20-month-old) C57BL/6 mice were subjected to an 8-week HIIT regimen. To elucidate the role of APJ in HIIT-induced cardiac adaptions, mice were randomly assigned to one of three groups: HIIT with cardiomyocyte-specific APJ knockdown via adeno-associated virus, HIIT with an empty vector, and a sedentary control group. Senescent cardiomyocytes were employed to assess the impact of Apelin-13 and SIRT3 modulation on mitochondrial function. Additionally, a pharmacological study was conducted in aged mice using the APJ agonist AMG986, with or without the SIRT3 inhibitor 3TYP, to evaluate its therapeutic potential. RESULTS: In aged mice, HIIT elevated myocardial APJ expression, resulting in improved cardiac function, reduced fibrosis and senescence, and preserved mitochondrial structure. Disruption of APJ/Apelin signaling pathway blunted these benefits, particularly impairing mitochondrial biogenesis, motility, mitophagy, and energy metabolism. In vitro, SIRT3 deficiency abolished Apelin-13-induced enhancements in mitochondrial membrane potential, respiratory capacity and morphology. In vivo, pharmacological activation of APJ reproduced key anti-aging cardiac effects, which were negated by SIRT3 inhibition. CONCLUSIONS: These findings suggested that HIIT exerted cardioprotective effects, at least in part, by enhancing apelinergic signaling and potentially modulating mitochondrial function through a SIRT3-dependent pathway. Targeting this pathway may provide potential therapeutic avenues for age-related cardiac dysfunction.