Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Department of Medicine, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
Nat Commun. 2021 Mar 15;12(1):1680. doi: 10.1038/s41467-021-21962-2.
Branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) are elevated in an array of cardiometabolic diseases. Here we demonstrate that the major metabolic fate of uniformly-C-labeled α-ketoisovalerate ([U-C]KIV) in the heart is reamination to valine. Activation of cardiac branched-chain α-ketoacid dehydrogenase (BCKDH) by treatment with the BCKDH kinase inhibitor, BT2, does not impede the strong flux of [U-C]KIV to valine. Sequestration of BCAA and BCKA away from mitochondrial oxidation is likely due to low levels of expression of the mitochondrial BCAA transporter SLC25A44 in the heart, as its overexpression significantly lowers accumulation of [C]-labeled valine from [U-C]KIV. Finally, exposure of perfused hearts to levels of BCKA found in obese rats increases phosphorylation of the translational repressor 4E-BP1 as well as multiple proteins in the MEK-ERK pathway, leading to a doubling of total protein synthesis. These data suggest that elevated BCKA levels found in obesity may contribute to pathologic cardiac hypertrophy via chronic activation of protein synthesis.
支链氨基酸（BCAA）及其相应的α-酮酸（BCKA）在一系列心血管代谢疾病中升高。在这里，我们证明了在心脏中，均匀标记的α-酮异戊酸（[U-C]KIV）的主要代谢命运是再氨基化为缬氨酸。用 BCKDH 激酶抑制剂 BT2 处理可激活心脏支链α-酮酸脱氢酶（BCKDH），但不会阻碍[U-C]KIV 向缬氨酸的强通量。BCAA 和 BCKA 远离线粒体氧化的隔离可能是由于心脏中线粒体 BCAA 转运蛋白 SLC25A44 的低表达水平，因为其过表达可显著降低从[U-C]KIV 中标记的[C]-缬氨酸的积累。最后，向灌注心脏中添加肥胖大鼠中发现的 BCKA 水平会增加翻译抑制剂 4E-BP1 的磷酸化以及 MEK-ERK 途径中的多种蛋白，导致总蛋白质合成增加一倍。这些数据表明，肥胖症中发现的升高的 BCKA 水平可能通过蛋白质合成的慢性激活导致病理性心肌肥大。
