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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Walejko, JM; Christopher, BA; Crown, SB; Zhang, G-F; Pickar-Oliver, A; Yoneshiro, T; Foster, MW; Page, S; van Vliet, S; Ilkayeva, O; Muehlbauer, MJ; Carson, MW; Brozinick, JT; Hammond, CD; Gimeno, RE; Moseley, MA; Kajimura, S; Gersbach, CA; Newgard, CB; White, PJ; McGarrah, RW

Published Date

  • March 15, 2021

Published In

Volume / Issue

  • 12 / 1

Start / End Page

  • 1680 -

PubMed ID

  • 33723250

Pubmed Central ID

  • 33723250

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-021-21962-2

Language

  • eng

Conference Location

  • England