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

Abstract

Summary 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 (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 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.

Identification of Energy Metabolism Changes in Diabetic Cardiomyopathy Rats Using a Metabonomic Approach

“…On the other hand, BCAAs can provide materials that drive energy production, and they play important roles in the maintenance and growth of muscle [44,45]. In the BCAA catabolic pathway, BCAAs are first converted into branched-chain alpha-ketoacids (BCKAs) by branched-chain amino-transferase (BCAT), followed by a decarboxylation reaction via branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, and eventually metabolized to acetyl-CoA for oxidation in the TCA cycle [46]. Recently, it has been reported that chronic accumulation of BCAAs downregulates the hexosamine biosynthetic pathway and inactivates pyruvate dehydrogenase, which is accompanied by decreases in glucose uptake, and protein glycosylation [46].…”

“…In the BCAA catabolic pathway, BCAAs are first converted into branched-chain alpha-ketoacids (BCKAs) by branched-chain amino-transferase (BCAT), followed by a decarboxylation reaction via branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, and eventually metabolized to acetyl-CoA for oxidation in the TCA cycle [46]. Recently, it has been reported that chronic accumulation of BCAAs downregulates the hexosamine biosynthetic pathway and inactivates pyruvate dehydrogenase, which is accompanied by decreases in glucose uptake, and protein glycosylation [46]. The results of that study identified a novel mechanism that enables defective BCAA catabolism to suppress glucose metabolism and sensitize the heart to hyperglycemic injury.…”

Bernard and Joan Marshall Awards at the autumn meeting of the British Society for Cardiovascular Research 2017

“…Returning to the GLUT1-overexpressing mouse heart, she showed that these hearts also maintained cardiac energetics and function under pressure overload, but that in this case the hearts still showed hypertrophy 7. Rong Tian then described recent work that investigated the effect of branched chain amino acid (BCAA) catabolism on cardiac energy metabolism and function using mice deficient in the serine–threonine protein phosphatase PP2Cm 8. Using a combination of phosphorous-31 and carbon-13 nuclear magnetic resonance (NMR) spectroscopy of isolated perfused mouse hearts, she showed that contractile function was similar in wild-type and PP2Cm-deficient hearts, and that the phosphocreatine-to-ATP ratio, an estimate of myocardial energetics, was also comparable between the two groups.…”

“…However, there was a switch towards increased fatty acid oxidation in the PP2Cm-deficient hearts resulting from a chronic accumulation of BCAA, which inhibited the pyruvate dehydrogenase complex activity. The PP2Cm-deficient mouse hearts were found to be vulnerable to ischaemia/reperfusion injury, but this could be rescued by increasing BCAA catabolism or by overexpressing GLUT1 and thereby normalising glucose use 8. Finally, she described recent work showing that elevated glucose levels decreased expression of Kruppel-like factor 15 (KLF15) and that this in turn downregulated BCAA degradation 9.…”

Rong Tian

“…More than just energy sources, Tian has produced evidence that these molecules act as signals, changing the way cells behave in critically important ways. [1][2][3] The heart consumes a tremendous amount of energy-at least 12× its weight in adenosine triphosphate each day. In healthy adults, fatty acids feed the heart, but glucose is the preferred energy source for both healthy fetal hearts and diseased adult hearts.…”