Running exercise alleviates chronic heart failure by promoting cardiomyocyte autophagic flux through the NEAT1–QKI affecting Beclin1/LC3B mRNA stability

As the end-stage manifestation of cardiovascular diseases (CVDs), chronic heart failure (CHF) is associated with high morbidity and mortality. Our previous study showed that Running exercise could improve CHF by inducing autophagy, but the underlying mechanisms and applicability remain unclear. This study investigated the roles of NEAT1 and RNA-binding protein Quaking (QKI) in the cardioprotective effects of running exercise initiated during the early stage after abdominal aortic coarctation (AAC) surgery. NEAT1 and QKI were overexpressed in vivo or NEAT1 and QKI were knocked down in vitro. The effects of running exercise on the myocardial damage of CHF rats or Ang II-induced cardiomyocyte apoptosis, autophagic flux, autophagy-related protein expression, and the expression of the PI3K/ AKT pathway by regulating NEAT1 and QKI were assessed using echocardiography, tissue staining, immunofluorescence, western blotting, and confocal microscopy. Furthermore, RNA immunoprecipitation (RIP), RBPmap prediction, actinomycin D (ActD) chase experiments and Dual-luciferase reporter assays were performed to explore the post-transcriptional regulation of autophagy-related genes by QKI. Running exercise reduced myocardial tissue damage in CHF rats and up-regulated the expression of autophagy-related proteins. NEAT1 was up-regulated in the myocardial tissue of CHF rats, and Ang II-damaged cardiomyocytes. Whereas QKI expression showed the opposite trend. Additionally, running exercise inhibited NEAT1 while restoring QKI expression, particularly during weeks 2-3 of exercise intervention. Mechanistically, NEAT1 directly interacted with QKI and negatively regulated its expression. Simultaneously, QKI bound to the 3'untranslated regions (3'-UTRs) of Beclin1 and LC3B mRNA and enhances the stability of Beclin1 and LC3B transcripts, thereby promoting autophagy. Functionally, NEAT1 inhibition or QKI upregulation suppressed the PI3K/AKT/mTOR signaling pathway, and attenuated cardiomyocyte apoptosis under pathological conditions. Collectively, the current findings revealed the regulatory mechanism by which running exercise alleviates CHF, and clarified that running promotes cardiomyocyte autophagy and alleviates CHF through the NEAT1-QKI-Beclin1/LC3B regulatory axis, highlighting a novel mechanism underlying exercise-mediated cardioprotection. Given that exercise intervention was initiated during the early stage following AAC surgery, the observed benefits may include early remodeling-modifying and disease-progression-modifying effects, rather than solely therapeutic effects on established decompensated CHF.