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

• Published in: Cell metabolism Vol. 25; no. 2; pp. 374 - 385
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-02-2017
• Subjects: Acetylglucosamine - metabolism; Amino Acids, Branched-Chain - metabolism; Animals; branched-chain amino acids; cardiac metabolism; glucose; Glucose - metabolism; Glycosylation; Heart Function Tests; ischemia-reperfusion; Mice, Inbred C57BL; Mice, Knockout; mitochondria; Mitochondria, Heart - metabolism; Myocardium - metabolism; Myocardium - pathology; N-glcNacation; pyruvate dehydrogenase; Pyruvate Dehydrogenase Complex - metabolism; Pyruvic Acid - metabolism; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; pyruvate dehydrogenase; glucose; cardiac metabolism; N-glcNacation; mitochondria; ischemia-reperfusion; branched-chain amino acids
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.11.005

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.
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•Branched-chain amino acid (BCAA) catabolism regulates glucose metabolism in the heart•High levels of BCAAs selectively disrupt mitochondrial pyruvate utilization•Downregulation of HBP by chronic accumulation of BCAAs inactivates PDH•Defective BCAA catabolism sensitizes the heart to ischemia-reperfusion insult
Branched-chain amino acids (BCAAs) have been implicated in cardiovascular disease. Li et al. now reveal molecular mechanisms behind BCAA catabolism in regulating cardiac metabolism and stress response. Chronic accumulation of BCAAs downregulates the hexosamine biosynthetic pathway and inactivates pyruvate dehydrogenase, which renders the heart vulnerable to ischemic injury.