Lowering Cardiac Branched-Chain Keto Acid Levels Enhances Cardiac Glucose Oxidation and Cardiac Efficiency via Enhancing Mitochondrial Insulin Signaling in Heart Failure.

Elevated levels of cardiac branched-chain amino acids (BCAAs) and their metabolites, namely branched-chain keto acids (BCKAs), contribute to the development of insulin resistance, contractile dysfunction, and adverse remodeling in the failing heart. However, there is still confusion about whether BCAA or BCKA mediate these detrimental effects in the failing heart. Cardiac-specific mitochondrial branched-chain aminotransferase, the enzyme that converts BCAA into BCKA, knockout (BCAT2-/-) mice underwent a sham or transverse aortic constriction surgery to induce heart failure. Changes in cardiac function and structure were monitored pre- and posttransverse aortic constriction using echocardiography, and metabolic flux through the tricarboxylic acid cycle was measured by perfusing isolated working hearts with radiolabeled energy substrates. Direct effects of BCAA and BCKA on cell hypertrophy were characterized using phenylephrine-induced cell hypertrophy in differentiated cells. Lowering cardiac BCKA levels in BCAT2-/- failing hearts increases insulin-stimulated glucose oxidation rates via enhancing mitochondrial protein kinase B and pyruvate dehydrogenase complex activities. Increased glucose oxidation rates in BCAT2-/- failing hearts enhanced cardiac efficiency by decreasing myocardial oxygen consumption rates. However, cardiac BCAA accumulation was associated with excessive stimulation of the mammalian target of rapamycin signaling and aggravation of adverse cardiac remodeling in BCAT2-/- failing hearts. As a result, the impact of BCAA accumulation offsets the beneficial effects of lowering cardiac BCKA levels on cardiac insulin sensitivity and cardiac efficiency. Lowering BCKA levels enhances cardiac glucose oxidation and cardiac efficiency by enhancing mitochondrial insulin signaling. BCAA accumulation worsens adverse cardiac remodeling by exacerbating cardiac mammalian target of rapamycin signaling.