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

Jacquelyn M. Walejko, Bridgette A. Christopher, Scott B. Crown, Guo-Fang Zhang, Adrian Pickar-Oliver, Takeshi Yoneshiro, Matthew W. Foster, Stephani Page, Stephan Vliet, Olga Ilkayeva, Michael J. Muehlbauer, Matthew W. Carson, Joseph T. Brozinick, Craig D. Hammond, Ruth E. Gimeno, M. Arthur Moseley, Shingo Kajimura, Charles A. Gersbach, Christopher B. Newgard, Phillip J. White () and Robert W. McGarrah ()
Additional contact information
Jacquelyn M. Walejko: Duke University School of Medicine
Bridgette A. Christopher: Duke University School of Medicine
Scott B. Crown: Duke University School of Medicine
Guo-Fang Zhang: Duke University School of Medicine
Adrian Pickar-Oliver: Duke University
Takeshi Yoneshiro: UCSF Diabetes Center
Matthew W. Foster: Duke University School of Medicine
Stephani Page: Duke University School of Medicine
Stephan Vliet: Duke University School of Medicine
Olga Ilkayeva: Duke University School of Medicine
Michael J. Muehlbauer: Duke University School of Medicine
Matthew W. Carson: Eli Lilly and Company
Joseph T. Brozinick: Eli Lilly and Company
Craig D. Hammond: Eli Lilly and Company
Ruth E. Gimeno: Eli Lilly and Company
M. Arthur Moseley: Duke University School of Medicine
Shingo Kajimura: UCSF Diabetes Center
Charles A. Gersbach: Duke University
Christopher B. Newgard: Duke University School of Medicine
Phillip J. White: Duke University School of Medicine
Robert W. McGarrah: Duke University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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-13C-labeled α-ketoisovalerate ([U-13C]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-13C]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 [13C]-labeled valine from [U-13C]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.

Date: 2021
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DOI: 10.1038/s41467-021-21962-2

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