Defective Branched Chain Amino Acids Catabolism Contributes To Post-myocardial Infarction Cardiac Dysfunction And Remodeling Through Activating MTOR Signaling

Cardiac metabolic remodeling is a central event in development of heart failure(HF) after myocardial infarction(MI). As well-known, glucose and fatty acids dysmetabolism in post-MI myocardium contributes to HF progression; however, the role of amino acid metabolism in post-MI HF remains largely elusive. Branched chain amino acids(BCAA) are a group of essential amino acids and function as crucial nutrient signaling in heart. Here we aimed to determine the role of BCAA metabolism in post-MI cardiac dysfunction and remodeling. Utilizing MI-induced murine HF models, we found that cardiac BCAA catabolism was significantly impaired following MI, therefore leading to an obvious elevation of myocardial BCAA. Oral BCAA administration further elevated cardiac BCAA abundance, activated mammalian target of rapamycin(mTOR), and exacerbated MI-induced cardiac dysfunction and remodeling, suggesting that BCAA act as a direct contributor to HF progression following MI. Moreover, BCAA-mediated deleterious effects were reversed by rapamycin co-treatment, revealing an essential role of mTOR signaling in BCAA-aggravated cardiac remodeling and dysfunction. Importantly, for the first time, we found that pharmacological inhibition of branched-chain-ketoacid dehydrogenase kinase(BDK), a negative regulator of cardiac BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA accumulation, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data demonstrate that defective myocardial BCAA catabolism contributes to post-MI cardiac dysfunction and remodeling, providing novel insight that improving cardiac BCAA catabolism may be a promising therapeutic strategy for HF after MI.