Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury

Tao Li, Zhen Zhang, Stephen C. Kolwicz, Lauren Abell, Nathan D. Roe, Maengjo Kim, Bo Zhou, Yang Cao, Julia Ritterhoff, Haiwei Gu, Daniel Raftery, Haipeng Sun, Rong Tian

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Elevated levels of branched-chain amino acids (BCAAs) have recently been implicated in the development of cardiovascular and metabolic diseases, but the molecular mechanisms are unknown. In a mouse model of impaired BCAA catabolism (knockout [KO]), we found that chronic accumulation of BCAAs suppressed glucose metabolism and sensitized the heart to ischemic injury. High levels of BCAAs selectively disrupted mitochondrial pyruvate utilization through inhibition of pyruvate dehydrogenase complex (PDH) activity. Furthermore, downregulation of the hexosamine biosynthetic pathway in KO hearts decreased protein O-linked N-acetylglucosamine (O-GlcNAc) modification and inactivated PDH, resulting in significant decreases in glucose oxidation. Although the metabolic remodeling in KO did not affect baseline cardiac energetics or function, it rendered the heart vulnerable to ischemia-reperfusion injury. Promoting BCAA catabolism or normalizing glucose utilization by overexpressing GLUT1 in the KO heart rescued the metabolic and functional outcome. These observations revealed a novel role of BCAA catabolism in regulating cardiac metabolism and stress response.

Original languageEnglish (US)
Pages (from-to)374-385
Number of pages12
JournalCell Metabolism
Volume25
Issue number2
DOIs
StatePublished - Feb 7 2017
Externally publishedYes

Fingerprint

Branched Chain Amino Acids
Reperfusion Injury
Glucose
Pyruvate Dehydrogenase Complex
Hexosamines
Acetylglucosamine
Biosynthetic Pathways
Metabolic Diseases
Pyruvic Acid
Cardiovascular Diseases
Down-Regulation
Wounds and Injuries
Proteins

Keywords

  • branched-chain amino acids
  • cardiac metabolism
  • glucose
  • ischemia-reperfusion
  • mitochondria
  • N-glcNacation
  • pyruvate dehydrogenase

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. / Li, Tao; Zhang, Zhen; Kolwicz, Stephen C.; Abell, Lauren; Roe, Nathan D.; Kim, Maengjo; Zhou, Bo; Cao, Yang; Ritterhoff, Julia; Gu, Haiwei; Raftery, Daniel; Sun, Haipeng; Tian, Rong.

In: Cell Metabolism, Vol. 25, No. 2, 07.02.2017, p. 374-385.

Research output: Contribution to journalArticle

Li, T, Zhang, Z, Kolwicz, SC, Abell, L, Roe, ND, Kim, M, Zhou, B, Cao, Y, Ritterhoff, J, Gu, H, Raftery, D, Sun, H & Tian, R 2017, 'Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury', Cell Metabolism, vol. 25, no. 2, pp. 374-385. https://doi.org/10.1016/j.cmet.2016.11.005
Li, Tao ; Zhang, Zhen ; Kolwicz, Stephen C. ; Abell, Lauren ; Roe, Nathan D. ; Kim, Maengjo ; Zhou, Bo ; Cao, Yang ; Ritterhoff, Julia ; Gu, Haiwei ; Raftery, Daniel ; Sun, Haipeng ; Tian, Rong. / Defective Branched-Chain Amino Acid Catabolism Disrupts Glucose Metabolism and Sensitizes the Heart to Ischemia-Reperfusion Injury. In: Cell Metabolism. 2017 ; Vol. 25, No. 2. pp. 374-385.
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