Karwi Qutuba G, Zhang Liyan, Gopal Keshav, Wagg Cory S, Ho Kim L, Sun Qiuyu, Panidarapu Sai, Persad Kaya, Altuany Betüol, Damen Shaden, Ketema Ezra, Levasseur Jody, Pulinilkunnil Thomas, Ussher John R, Dyck Jason R B, Lopaschuk Gary D
Department of Pharmacology, College of Medicine, University of Diyala, Baqubaa, Iraq (Q.G.K.).
Cardiovascular Research Centre (Q.G.K., L.Z., C.S.W., K.L.H., Q.S., S.P., K.P., B.A., S.D., E.K., J.L., J.R.B.D., G.D.L.), University of Alberta, Edmonton, AB, Canada.
Circ Heart Fail. 2025 Sep;18(9):e012012. doi: 10.1161/CIRCHEARTFAILURE.124.012012. Epub 2025 Jul 25.
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.
心脏中支链氨基酸（BCAAs）及其代谢产物，即支链酮酸（BCKAs）水平升高，会导致胰岛素抵抗、收缩功能障碍以及衰竭心脏的不良重塑。然而，关于在衰竭心脏中是BCAA还是BCKA介导这些有害作用仍存在困惑。
心脏特异性线粒体支链氨基转移酶是一种将BCAA转化为BCKA的酶，敲除（BCAT2）小鼠接受假手术或横断主动脉缩窄手术以诱导心力衰竭。使用超声心动图监测横断主动脉缩窄前后的心脏功能和结构变化，并通过用放射性标记的能量底物灌注离体工作心脏来测量三羧酸循环的代谢通量。使用去甲肾上腺素诱导分化细胞肥大来表征BCAA和BCKA对细胞肥大的直接影响。
降低BCAT2衰竭心脏中的BCKA水平，通过增强线粒体蛋白激酶B和丙酮酸脱氢酶复合物的活性，提高胰岛素刺激的葡萄糖氧化速率。BCAT2衰竭心脏中葡萄糖氧化速率的增加通过降低心肌耗氧率提高心脏效率。然而，心脏BCAA的积累与雷帕霉素信号转导的哺乳动物靶点的过度刺激以及BCAT2衰竭心脏中不良心脏重塑的加重有关。因此，BCAA积累的影响抵消了降低心脏BCKA水平对心脏胰岛素敏感性和心脏效率的有益作用。
降低BCKA水平通过增强线粒体胰岛素信号转导来提高心脏葡萄糖氧化和心脏效率。BCAA积累通过加剧心脏雷帕霉素信号转导的哺乳动物靶点而使不良心脏重塑恶化。
