Journal Article

Branched-chain α-ketoacids are preferentially reaminated and activate protein synthesis in the heart

Walejko, Jacquelyn M., Kajimura, Shingo, Yoneshiro, Takeshi, Muehlbauer, Michael J., Gersbach, Charles A., Carson, Matthew W., White, Phillip J., Foster, Matthew W., Crown, Scott B., Newgard, Christopher B., Pickar-Oliver, Adrian, van Vliet, Stephan, Moseley, M. Arthur, Brozinick, Joseph T., Ilkayeva, Olga, Gimeno, Ruth E., Christopher, Bridgette A., Zhang, Guo-Fang, Hammond, Craig D., Page, Stephani, McGarrah, Robert W.

2021

Overview

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- 13 C-labeled α-ketoisovalerate ([U- 13 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- 13 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 [ 13 C]-labeled valine from [U- 13 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. Systemic modulation of branched-chain keto acid (BCKA) metabolism alters cardiac health. Here, the authors define the major fates of BCKA in the heart and demonstrate that acute exposure to BCKA levels found in obesity activates cardiac protein synthesis and markedly alters the heart phosphoproteome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/443/319 / 631/443/592/1540 / 631/45/320 / 82/58 / Amino acids / Amino Acids, Branched-Chain - metabolism / Animals / Chain branching / Chains / Enzyme inhibitors / Extracellular signal-regulated kinase / Heart / Heart - physiology / Hemiterpenes - metabolism / Humanities and Social Sciences / Hypertrophy / Keto Acids - metabolism / Kinases / Male / Metabolic pathways / Mice / Mice, Inbred C57BL / Mitochondria / Mitochondria - metabolism / multidisciplinary / Obesity / Obesity - metabolism / Oxidation / Phosphorylation / Protein biosynthesis / Protein synthesis / Proteins / Rats / Science / Science (multidisciplinary) / Valine / Valine - metabolism