Metabolic remodeling is an integral part of heart failure. Although glucose and fatty acids metabolism have been extensively studied, little is known about the role of amino acids homeostasis in heart physiology and pathology. Branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for both protein synthesis and cellular signaling. Elevated levels of BCAAs have been linked with heart failure. However, the underlying regulatory mechanism and functional significance of abnormal BCAA catabolism in heart failure have not been established. We found that genes involved in BCAA catabolism, including a key regulatory protein PP2Cm, are significantly down-regulated at mRNA as well as protein level in pressure-overload induced failing heart in mice. Furthermore, the concentrations of BCAA catabolic products branched-chain keto acids (BCKAs) are also elevated in heart tissues of post TAC mice. Interestingly, the down-regulation of BCAA catabolic genes mimics a similar expression pattern observed in fetal heart, suggesting that decreased BCAA catabolic activity is part of the metabolic remodeling in pathologically stressed heart from an adult to a fetal-like state. Genetic ablation of PP2Cm in mouse leads to defect in BCAA catabolism and accumulation of BCAAs and BCKAs in cardiac tissue and serum. PP2Cm deficient mice had lower cardiac contractility and higher susceptibility to develop heart failure under pressure overload. In addition, BCKAs treatment to isolated mitochondria resulted in lower oxygen consumption rate and ATP production. PP2Cm deficiency as well as BCKAs treatment induced oxidative stress in cardiomyocyte and antioxidant treatment ameliorated the development of heart failure in PP2Cm deficient animals. Together, these data indicated that BCAA catabolic remodeling is likely an integrated component of metabolic remodeling during heart failure. More importantly, mis-regulation of BCAA catabolism in heart promoted heart failure progression, involving direct impact on mitochondrial function and redox homeostasis in cardiomyocytes.
Impact of Melatonin and Branched-Chain Amino Acids Cosupplementation on Quality of Life, Fatigue, and Nutritional Status in Cachectic Heart Failure Patients: A Randomized Controlled Trial
