Exercise training attenuates cardiac dysfunction induced by excessive sympathetic system activation through an AMPK-KLF4-FMO2 axis

Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide and are associated with an overactivated sympathetic system. Exercise training has been reported to ameliorate sympathetic stress-induced cardiac remodeling in CVD, however the underlying mechanisms remain elusive. Here, we have carried out a multidisciplinary investigation to discover that exercise significantly upregulates cardiac FMO2 expression. Notably, we find that exercise training effectively mitigates sympathetic overactivation-induced cardiac dysfunction and fibrosis by enhancing FMO2 expression via AMPK activation. Our functional analysis utilizing FMO2 knockdown with adeno-associated virus 9 (AAV9) in mice in vivo demonstrates that FMO2 expression is protective for heart tissue during exercise. Furthermore, we find that the transcription factor KLF4 binds to the FMO2 promoter to potentiate its expression, and this activity is important for mediating AMPK activation that is protective against sympathetic overactivation-induced cardiac dysfunction and fibrosis. Taken together, our study finds that exercise training exerts cardioprotective effects through an AMPK-KLF4-FMO2 signaling pathway that is important for mediating the cardioprotective effects of exercise.