Exercise alleviates programmed necrosis in myocardial ischemia-reperfusion injury through adipose tissue-derived exosomal miR-17-3p targeting CAMKII.

Exercise exerts cardioprotective effects, with prior research implicating exosomal miR-17-3p as a critical mediator in attenuating myocardial ischemia-reperfusion injury (MIRI). The present study aimed to elucidate the influence of exercise on exosomal miR-17-3p and to delineate the underly mechanisms by which it mitigates MIRI. A MIRI model was established using C57BL/6 mice. Exosomes were isolated and their impact on programmed necrosis, cardiac function, infarct size, inflammatory factors (LDH, TNF-α), as well as proteins associated with ventricular remodeling, was evaluated. Complementary in vitro experiments employed primary cardiomyocytes to further investigate these effects. The regulatory relationship between miR-17-3p and calcium/calmodulin-dependent protein kinase II (CAMK II) was examined. Additionally, the contribution of brown adipose tissue (BAT) as the source of exosomal miR-17-3p was assessed. Findings demonstrated that exercise enhanced cardiac function and reduced infarct size in MIRI mice through exosome-mediated mechanisms. Mechanistically, exosomal miR-17-3p directly targeted CAMKII, leading to inhibition of the RIPK3/MLKL pathway, thereby attenuating cardiomyocyte necrosis and inflammation and reversing pathological ventricular remodeling. BAT was identified as the principal origin of exosomal miR-17-3p, and ablation of BAT abrogated the cardioprotective effects conferred by exercise. Collectively, these results suggest that exercise confers protection against MIRI by promoting the uptake of BAT-derived exosomal miR-17-3p uptake by cardiomyocytes, which in turn supresses CAMKII activity and programmed necrosis. This study reveals a novel exercise-induced cardioprotective pathway and identifies potential therapeutic targets for MIRI.