Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.

Journal Article (Journal Article)

BACKGROUND: Although metabolic reprogramming is critical in the pathogenesis of heart failure, studies to date have focused principally on fatty acid and glucose metabolism. Contribution of amino acid metabolic regulation in the disease remains understudied. METHODS AND RESULTS: Transcriptomic and metabolomic analyses were performed in mouse failing heart induced by pressure overload. Suppression of branched-chain amino acid (BCAA) catabolic gene expression along with concomitant tissue accumulation of branched-chain α-keto acids was identified as a significant signature of metabolic reprogramming in mouse failing hearts and validated to be shared in human cardiomyopathy hearts. Molecular and genetic evidence identified the transcription factor Krüppel-like factor 15 as a key upstream regulator of the BCAA catabolic regulation in the heart. Studies using a genetic mouse model revealed that BCAA catabolic defect promoted heart failure associated with induced oxidative stress and metabolic disturbance in response to mechanical overload. Mechanistically, elevated branched-chain α-keto acids directly suppressed respiration and induced superoxide production in isolated mitochondria. Finally, pharmacological enhancement of branched-chain α-keto acid dehydrogenase activity significantly blunted cardiac dysfunction after pressure overload. CONCLUSIONS: BCAA catabolic defect is a metabolic hallmark of failing heart resulting from Krüppel-like factor 15-mediated transcriptional reprogramming. BCAA catabolic defect imposes a previously unappreciated significant contribution to heart failure.

Full Text

Duke Authors

Cited Authors

  • Sun, H; Olson, KC; Gao, C; Prosdocimo, DA; Zhou, M; Wang, Z; Jeyaraj, D; Youn, J-Y; Ren, S; Liu, Y; Rau, CD; Shah, S; Ilkayeva, O; Gui, W-J; William, NS; Wynn, RM; Newgard, CB; Cai, H; Xiao, X; Chuang, DT; Schulze, PC; Lynch, C; Jain, MK; Wang, Y

Published Date

  • May 24, 2016

Published In

Volume / Issue

  • 133 / 21

Start / End Page

  • 2038 - 2049

PubMed ID

  • 27059949

Pubmed Central ID

  • PMC4879058

Electronic International Standard Serial Number (EISSN)

  • 1524-4539

Digital Object Identifier (DOI)

  • 10.1161/CIRCULATIONAHA.115.020226


  • eng

Conference Location

  • United States