BMP10 attenuates age-related atrial fibrillation susceptibility through improving mitochondrial function in atrial cardiomyocytes

BACKGROUND: Although emerging clinical studies exhibit a strong association of circulating bone morphogenetic protein (BMP10) level with adverse outcomes in patients with atrial fibrillation (AF), also in older individuals. The exact role of BMP10 in age-related AF pathogenesis and potential mechanisms remain unknown. METHODS: Aged rats were subjected to injection of negative control (NC) or adeno-associated virus 9 (AAV9) to overexpress BMP10, then intracardiac electrophysiology, echocardiography and histology were performed after 4 weeks. Proteomics was conducted to reveal the differential proteins in rat atria. Mitochondrial morphology, reactive oxygen species (ROS) and metabolic substrates were assessed by transmission electron microscopy, mitoSOX and testing assay. RESULTS: Aged rats and AF patients exhibited elevated serum BMP10 levels compared to young controls. Increased BMP10 protein expression correlated with atrial remodeling and AF phenotype of aged rats compared to young rats. Overexpression of BMP10 mitigated the pacing-induced AF incidence and increased conduction velocity compared to controls. Atrial fibrosis, inflammatory foci were reduced with restored electrical activity in AAV-BMP10 treated rats. Proteomics indicated improved atrial mitochondrial metabolism related to signal transducer and activator of transcription 3 (STAT3) signaling in AAV-BMP10 injection rats. Overexpressing BMP10 diminished ROS production by regulating phosphorylation of STAT3 translocation into mitochondria. Moreover, overexpressing BMP10 stimulated mitochondrial electron transport chain complexes to generate more ATP by upregulating biogenesis makers in atrial cardiomyocytes. CONCLUSIONS: Our work demonstrates that BMP10 alleviates age-related atrial arrhythmogenesis via mitochondrial STAT3 impacts in atrial cardiomyocytes.