1932

Abstract

Branched chain amino acids (BCAAs) are building blocks for all life-forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-020518-114455
2019-02-10
2024-04-25
Loading full text...

Full text loading...

/deliver/fulltext/physiol/81/1/annurev-physiol-020518-114455.html?itemId=/content/journals/10.1146/annurev-physiol-020518-114455&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Davis TA, Fiorotto ML, Reeds PJ 1993. Amino acid compositions of body and milk protein change during the suckling period in rats. J. Nutr. 123:5947–56
    [Google Scholar]
  2. 2.
    Harper A, Block K, Cree T 1983. Branched-chain amino acids: nutritional and metabolic interrelationships. Proceedings of the Fourth Symposium on Protein Metabolism and Nutrition R Pion, M Arnal, D Bonin 159–81 Paris: INRA
    [Google Scholar]
  3. 3.
    Moura A, Savageau MA, Alves R 2013. Relative amino acid composition signatures of organisms and environments. PLOS ONE 8:10e77319
    [Google Scholar]
  4. 4.
    Chou PY, Fasman GD 1973. Structural and functional role of leucine residues in proteins. J. Mol. Biol. 74:3263–81
    [Google Scholar]
  5. 5.
    Dill KA. 1990. Dominant forces in protein folding. Biochemistry 29:317133–55
    [Google Scholar]
  6. 6.
    Schweigert BS, Bennett BA, Guthneck BT 1954. Amino acid composition of organ meats. J. Food Sci. 19:1–6219–23
    [Google Scholar]
  7. 7.
    Brosnan JT, Brosnan ME 2006. Branched-chain amino acids: enzyme and substrate regulation. J. Nutr. 136:1207S–11S
    [Google Scholar]
  8. 8.
    Shimomura Y, Obayashi M, Murakami T, Harris RA 2001. Regulation of branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain α-keto acid dehydrogenase kinase. Curr. Opin. Clin. Nutr. Metab. Care 4:5419–23
    [Google Scholar]
  9. 9.
    McCourt JA, Duggleby RG 2006. Acetohydroxyacid synthase and its role in the biosynthetic pathway for branched-chain amino acids. Amino Acids 31:2173–210
    [Google Scholar]
  10. 10.
    Amorim Franco TM, Blanchard JS 2017. Bacterial branched-chain amino acid biosynthesis: structures, mechanisms, and drugability. Biochemistry 56:445849–65
    [Google Scholar]
  11. 11.
    Ichihara A, Koyama E 1966. Transaminase of branched chain amino acids. J. Biochem. 59:2160–69
    [Google Scholar]
  12. 12.
    Ichihara A, Yamasaki Y, Masuji H, Sato J 1975. Isozyme patterns of branched chain amino acid transaminase during cellular differentiation and carcinogenesis. Isozymes 3 CL Markert 875–89 Amsterdam: Elsevier
    [Google Scholar]
  13. 13.
    Kadowaki H, Knox WE 1982. Cytoslic and mitochondrial isoenzymes of branched-chain amino acid aminotransferase during development of the rat. Biochem. J. 202:777–83
    [Google Scholar]
  14. 14.
    Krebs HA, Lund P 1977. Aspects of the regulation of the metabolism of branched-chain amino acids. Adv. Enzyme Regul. 15:375–94
    [Google Scholar]
  15. 15.
    Goto M, Shinno H, Ichihara A 1977. Isozyme patterns of branched-chain amino acid transaminase in human tissues and tumors. GANN Jpn. J. Cancer Res. 68:5663–67
    [Google Scholar]
  16. 16.
    Patel MS, Nemeria NS, Furey W, Jordan F 2014. The pyruvate dehydrogenase complexes: structure-based function and regulation. J. Biol. Chem. 289:2416615–23
    [Google Scholar]
  17. 17.
    Wieland OH. 1983. The mammalian pyruvate dehydrogenase complex: structure and regulation. Reviews of Physiology, Biochemistry and Pharmacology 96 RH Adrian, H zur Hausen, E Helmreich, H Holzer, R Jung et al.123–70 Berlin: Springer
    [Google Scholar]
  18. 18.
    Johnson WA, Connelly JL, Glynn MT 1972. Cellular localization and characterization of bovine liver branched-chain α-keto acid dehydrogenases. Biochemistry 11:101967–73
    [Google Scholar]
  19. 19.
    Paxton R, Harris RA 1982. Isolation of rabbit liver branched chain α-ketoacid dehydrogenase and regulation by phosphorylation. J. Biol. Chem. 257:314433–39
    [Google Scholar]
  20. 20.
    Pettit FH, Yeaman SJ, Reed LJ 1978. Purification and characterization of branched chain α-keto acid dehydrogenase complex of bovine kidney. PNAS 75:104881–85
    [Google Scholar]
  21. 21.
    Danner DJ, Lemmon SK, Elsas LJ II. 1978. Substrate specificity and stabilization by thiamine pyrophosphate of rat liver branched chain α-ketoacid dehydrogenase. Biochem. Med. 19:127–38
    [Google Scholar]
  22. 22.
    Babady NE, Pang Y-P, Elpeleg O, Isaya G 2007. Cryptic proteolytic activity of dihydrolipoamide dehydrogenase. PNAS 104:156158–63
    [Google Scholar]
  23. 23.
    Harris RA, Popov KM, Shimomura Y, Zhao Y, Jaskiewicz J et al. 1992. Purification, characterization, regulation and molecular cloning of mitochondrial protein kinases. Adv. Enzyme Regul. 32:267–84
    [Google Scholar]
  24. 24.
    Popov KM, Shimomura Y, Harris RA 1991. Purification and comparative study of the kinases specific for branched chain α-ketoacid dehydrogenase and pyruvate dehydrogenase. Protein Expr. Purif. 2:4278–86
    [Google Scholar]
  25. 25.
    Popov KM, Zhao Y, Shimomura Y, Kuntz MJ, Harris RA 1992. Branched-chain α-ketoacid dehydrogenase kinase. Molecular cloning, expression, and sequence similarity with histidine protein kinases. J. Biol. Chem. 267:1913127–30
    [Google Scholar]
  26. 26.
    Shimomura Y, Nanaumi N, Suzuki M, Popov KM, Harris RA 1990. Purification and partial characterization of branched-chain α-ketoacid dehydrogenase kinase from rat liver and rat heart. Arch. Biochem. Biophys. 283:2293–99
    [Google Scholar]
  27. 27.
    Tuor U, Simone C, Bascaramurty S 1992. Local blood‐brain barrier in the newborn rabbit: postnatal changes in α‐aminoisobutyric acid transfer within medulla, cortex, and selected brain areas. J. Neurochem. 59:3999–1007
    [Google Scholar]
  28. 28.
    Damuni Z, Reed LJ 1987. Purification and properties of the catalytic subunit of the branched-chain α-keto acid dehydrogenase phosphatase from bovine kidney mitochondria. J. Biol. Chem. 262:115129–32
    [Google Scholar]
  29. 29.
    Damuni Z, Merryfield ML, Humphreys JS, Reed LJ 1984. Purification and properties of branched-chain α-keto acid dehydrogenase phosphatase from bovine kidney. PNAS 81:144335–38
    [Google Scholar]
  30. 30.
    Crowell PL, Block KP, Repa JJ, Torres N, Nawabi MD et al. 1990. High branched-chain α-keto acid intake, branched chain α-keto acid dehydrogenase activity, and plasma and brain amino acid and plasma keto acid concentrations in rats. Am. J. Clin. Nutr. 52:2313–19
    [Google Scholar]
  31. 31.
    Frick G, Tai L, Blinder L, Goodman H 1981. l-leucine activates branched chain α-keto acid dehydrogenase in rat adipose tissue. J. Biol. Chem. 256:62618–20
    [Google Scholar]
  32. 32.
    Lau KS, Fatania HR, Randle PJ 1982. Regulation of the branched chain 2‐oxoacid dehydrogenase kinase reaction. FEBS Lett 144:157–62
    [Google Scholar]
  33. 33.
    Waymack P, DeBuysere M, Olson M 1980. Studies on the activation and inactivation of the branched chain α-keto acid dehydrogenase in the perfused rat heart. J. Biol. Chem. 255:209773–81
    [Google Scholar]
  34. 34.
    Islam MM, Nautiyal M, Wynn RM, Mobley JA, Chuang DT, Hutson SM 2010. Branched-chain amino acid metabolon, interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm). J. Biol. Chem. 285:1265–76
    [Google Scholar]
  35. 35.
    Green CR, Wallace M, Divakaruni AS, Phillips SA, Murphy AN et al. 2016. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat. Chem. Biol. 12:115–21
    [Google Scholar]
  36. 36.
    Liebich HM, Först C 1984. Hydroxycarboxylic and oxocarboxylic acids in urine: products from branched-chain amino acid degradation and from ketogenesis. J. Chromatogr. B Biomed. Sci. Appl. 309:225–42
    [Google Scholar]
  37. 37.
    Anderson KA, Huynh FK, Fisher-Wellman K, Stuart JD, Peterson BS et al. 2017. SIRT4 is a lysine deacylase that controls leucine metabolism and insulin secretion. Cell Metab 25:4838–55
    [Google Scholar]
  38. 38.
    Jones JM, Morrell JC, Gould SJ 2000. Identification and characterization of HAOX1, HAOX2, and HAOX3, three human peroxisomal 2-hydroxy acid oxidases. J. Biol. Chem. 275:1712590–97
    [Google Scholar]
  39. 39.
    Van Koevering M, Nissen S 1992. Oxidation of leucine and alpha-ketoisocaproate to beta-hydroxy-beta-methylbutyrate in vivo. Am. J. Physiol. Endocrinol. Metab. 262:1E27–31
    [Google Scholar]
  40. 40.
    Long JZ, Svensson KJ, Bateman LA, Lin H, Kamenecka T et al. 2016. The secreted enzyme PM20D1 regulates lipidated amino acid uncouplers of mitochondria. Cell 166:2424–35
    [Google Scholar]
  41. 41.
    Crown SB, Marze N, Antoniewicz MR 2015. Catabolism of branched chain amino acids contributes significantly to synthesis of odd-chain and even-chain fatty acids in 3T3-L1 adipocytes. PLOS ONE 10:12e0145850
    [Google Scholar]
  42. 42.
    Wallace M, Green CR, Roberts LS, Lee YM, McCarville JL et al. 2018. Enzyme promiscuity drives branched-chain fatty acid synthesis in adipose tissues. Nat. Chem. Biol. 14:1021–31
    [Google Scholar]
  43. 43.
    Mika A, Stepnowski P, Kaska L, Proczko M, Wisniewski P et al. 2016. A comprehensive study of serum odd- and branched-chain fatty acids in patients with excess weight: odd- and branched-chain fatty acids in obesity. Obesity 24:81669–76
    [Google Scholar]
  44. 44.
    Ran-Ressler RR, Devapatla S, Lawrence P, Brenna JT 2008. Branched chain fatty acids are constituents of the normal healthy newborn gastrointestinal tract. Pediatr. Res. 64:6605–9
    [Google Scholar]
  45. 45.
    Buse MG, Reid SS 1975. Leucine. A possible regulator of protein turnover in muscle. J. Clin. Investig. 56:51250–61
    [Google Scholar]
  46. 46.
    Chang Hong S-O, Layman DK 1984. Effects of leucine on in vitro protein synthesis and degradation in rat skeletal muscles. J. Nutr. 114:71204–12
    [Google Scholar]
  47. 47.
    Li JB, Jefferson LS 1978. Influence of amino acid availability on protein turnover in perfused skeletal muscle. Biochim. Biophys. Acta 544:2351–59
    [Google Scholar]
  48. 48.
    Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM et al. 2015. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351:43–48
    [Google Scholar]
  49. 49.
    Saxton RA, Knockenhauer KE, Wolfson RL, Chantranupong L, Pacold ME et al. 2016. Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351:626853–58
    [Google Scholar]
  50. 50.
    Bonfils G, Jaquenoud M, Bontron S, Ostrowicz C, Ungermann C, De Virgilio C 2012. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell 46:1105–10
    [Google Scholar]
  51. 51.
    Han JM, Jeong SJ, Park MC, Kim G, Kwon NH et al. 2012. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149:2410–24
    [Google Scholar]
  52. 52.
    Yoon M-S, Son K, Arauz E, Han JM, Kim S, Chen J 2016. Leucyl-tRNA synthetase activates Vps34 in amino acid-sensing mTORC1 signaling. Cell Rep 16:61510–17
    [Google Scholar]
  53. 53.
    Efeyan A, Zoncu R, Sabatini DM 2012. Amino acids and mTORC1: from lysosomes to disease. Trends Mol. Med. 18:9524–33
    [Google Scholar]
  54. 54.
    Jewell JL, Russell RC, Guan K-L 2013. Amino acid signalling upstream of mTOR. Nat. Rev. Mol. Cell Biol. 14:3133–39
    [Google Scholar]
  55. 55.
    Laplante M, Sabatini DM 2012. mTOR signaling in growth control and disease. Cell 149:2274–93
    [Google Scholar]
  56. 56.
    Wolfson RL, Sabatini DM 2017. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab 26:2301–9
    [Google Scholar]
  57. 57.
    Christensen HN, Hellman B, Sehlin J, Tager HS, Täljedal I-B 1971. In vitro stimulation of insulin release by non-metabolizable, transport-specific amino acids. Biochim. Biophys. Acta Biomembr. 241:2341–48
    [Google Scholar]
  58. 58.
    Fajans SS, Quibrera R, Pek S, Floyd J, Christensen HN et al. 1971. Stimulation of insulin release in the dog by a nonmetabolizable amino acid. Comparison with leucine and arginine. J. Clin. Endocrinol. Metab. 33:135–41
    [Google Scholar]
  59. 59.
    Sener A, Malaisse WJ 1980. l-leucine and a nonmetabolized analogue activate pancreatic islet glutamate dehydrogenase. Nature 288:5787187–89
    [Google Scholar]
  60. 60.
    Gao ZY, Li G, Najafi H, Wolf BA, Matschinsky FM 1999. Glucose regulation of glutaminolysis and its role in insulin secretion. Diabetes 48:81535–42
    [Google Scholar]
  61. 61.
    Wilson DF, Cember ATJ, Matschinsky FM 2018. Glutamate dehydrogenase: role in regulating metabolism and insulin release in pancreatic β-cells. J. Appl. Physiol. 125:2419–28
    [Google Scholar]
  62. 62.
    Stanley CA, Lieu YK, Hsu BYL, Burlina AB, Greenberg CR et al. 1998. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N. Engl. J. Med. 338:191352–57
    [Google Scholar]
  63. 63.
    Gao Z, Young RA, Li G, Najafi H, Buettger C et al. 2003. Distinguishing features of leucine and α-ketoisocaproate sensing in pancreatic β-cells. Endocrinology 144:51949–57
    [Google Scholar]
  64. 64.
    Bränström R, Efendic S, Berggren P-O, Larsson O 1998. Direct inhibition of the pancreatic β-cell ATP-regulated potassium channel by α-ketoisocaproate. J. Biol. Chem. 273:2314113–18
    [Google Scholar]
  65. 65.
    Jang C, Oh SF, Wada S, Rowe GC, Liu L et al. 2016. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat. Med. 22:4421–26
    [Google Scholar]
  66. 66.
    Roberts LD, Boström P, O'Sullivan JF, Schinzel RT, Lewis GD et al. 2014. β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab 19:196–108
    [Google Scholar]
  67. 67.
    Kitase Y, Vallejo JA, Gutheil W, Vemula H, Jähn K et al. 2018. β-Aminoisobutyric acid, l -BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep 22:61531–44
    [Google Scholar]
  68. 68.
    Shi C-X, Zhao M-X, Shu X-D, Xiong X-Q, Wang J-J et al. 2016. β-Aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes. Sci. Rep. 6:21924
    [Google Scholar]
  69. 69.
    Jung TW, Park HS, Choi GH, Kim D, Lee T 2018. β-Aminoisobutyric acid attenuates LPS-induced inflammation and insulin resistance in adipocytes through AMPK-mediated pathway. J. Biomed. Sci. 25:127
    [Google Scholar]
  70. 70.
    Everman S, Mandarino LJ, Carroll CC, Katsanos CS 2015. Effects of acute exposure to increased plasma branched-chain amino acid concentrations on insulin-mediated plasma glucose turnover in healthy young subjects. PLOS ONE 10:3e0120049
    [Google Scholar]
  71. 71.
    Louard RJ, Barrett EJ, Gelfand RA 1990. Effect of infused branched-chain amino acids on muscle and whole-body amino acid metabolism in man. Clin. Sci. 79:5457–66
    [Google Scholar]
  72. 72.
    Wahren J, Felig P, Hagenfeldt L 1976. Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus. J. Clin. Investig. 57:4987–99
    [Google Scholar]
  73. 73.
    Grimble G. 2000. Mechanisms of peptide and amino acid transport and their regulation. Proteins, Peptides and Amino Acids in Enteral Nutrition P Fürst, V Young 63–88 Basel: Karger
    [Google Scholar]
  74. 74.
    Boirie Y, Dangin M, Gachon P, Vasson M-P, Maubois J-L, Beaufrère B 1997. Slow and fast dietary proteins differently modulate postprandial protein accretion. PNAS 94:2614930–35
    [Google Scholar]
  75. 75.
    Dangin M, Boirie Y, Garcia-Rodenas C, Gachon P, Fauquant J et al. 2001. The digestion rate of protein is an independent regulating factor of postprandial protein retention. Am. J. Physiol. Endocrinol. Metab. 280:2E340–48
    [Google Scholar]
  76. 76.
    Wolfe RR, Cifelli AM, Kostas G, Kim I-Y 2017. Optimizing protein intake in adults: interpretation and application of the recommended dietary allowance compared with the acceptable macronutrient distribution range. Adv. Nutr. Int. Rev. J. 8:2266–75
    [Google Scholar]
  77. 77.
    Fulgoni VL. 2008. Current protein intake in America: analysis of the National Health and Nutrition Examination Survey,. 2003–2004 Am. J. Clin. Nutr. 87:51554S–57S
    [Google Scholar]
  78. 78.
    Bier DM. 1989. Intrinsically difficult problems: the kinetics of body proteins and amino acids in man. Diabetes/Metab. Rev. 5:2111–32
    [Google Scholar]
  79. 79.
    Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X et al. 2017. Glucose feeds the TCA cycle via circulating lactate. Nature 551:115–18
    [Google Scholar]
  80. 80.
    Matthews DE, Motil KJ, Rohrbaugh DK, Burke JF, Young VR, Bier DM 1980. Measurement of leucine metabolism in man from a primed, continuous infusion of L-[1-13C] leucine. Am. J. Physiol. Endocrinol. Metab. 238:5E473–79
    [Google Scholar]
  81. 81.
    Wolfe RR, Goodenough RD, Wolfe MH, Royle GT, Nadel ER 1982. Isotopic analysis of leucine and urea metabolism in exercising humans. J. Appl. Physiol. 52:2458–66
    [Google Scholar]
  82. 82.
    Short KR, Vittone JL, Bigelow ML, Proctor DN, Nair KS 2004. Age and aerobic exercise training effects on whole body and muscle protein metabolism. Am. J. Physiol. Endocrinol. Metab. 286:1E92–101
    [Google Scholar]
  83. 83.
    Waterlow JC. 2006. Protein Turnover Wallingford, UK: CABI
  84. 84.
    May ME, Buse MG 1989. Effects of branched‐chain amino acids on protein turnover. Diabetes/Metab. Rev. 5:3227–45
    [Google Scholar]
  85. 85.
    Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR 2000. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J. Nutr. 130:102413–19
    [Google Scholar]
  86. 86.
    Anthony JC, Lang CH, Crozier SJ, Anthony TG, MacLean DA et al. 2002. Contribution of insulin to the translational control of protein synthesis in skeletal muscle by leucine. Am. J. Physiol. Endocrinol. Metab. 282:5E1092–101
    [Google Scholar]
  87. 87.
    Wang X, Proud CG 2006. The mTOR pathway in the control of protein synthesis. Physiology 21:5362–69
    [Google Scholar]
  88. 88.
    Nygren J, Nair KS 2003. Differential regulation of protein dynamics in splanchnic and skeletal muscle beds by insulin and amino acids in healthy human subjects. Diabetes 52:61377–85
    [Google Scholar]
  89. 89.
    James HA, O'Neill BT, Nair KS 2017. Insulin regulation of proteostasis and clinical implications. Cell Metab 26:2310–23
    [Google Scholar]
  90. 90.
    Rooyackers OE, Nair KS 1997. Hormonal regulation of human muscle protein metabolism. Annu. Rev. Nutr. 17:1457–85
    [Google Scholar]
  91. 91.
    Biolo G, Tipton KD, Klein S, Wolfe RR 1997. An abundant supply of amino acids enhances the metabolic effect of exercise on muscle protein. Am. J. Physiol. Endocrinol. Metab. 273:1E122–29
    [Google Scholar]
  92. 92.
    Shad BJ, Thompson JL, Breen L 2016. Does the muscle protein synthetic response to exercise and amino acid-based nutrition diminish with advancing age? A systematic review. Am. J. Physiol. Endocrinol. Metab. 311:5E803–17
    [Google Scholar]
  93. 93.
    Stokes T, Hector A, Morton R, McGlory C, Phillips S 2018. Recent perspectives regarding the role of dietary protein for the promotion of muscle hypertrophy with resistance exercise training. Nutrients 10:2180
    [Google Scholar]
  94. 94.
    Fryburg DA, Barrett EJ, Louard RJ, Gelfand RA 1990. Effect of starvation on human muscle protein metabolism and its response to insulin. Am. J. Physiol. Endocrinol. Metab. 259:4E477–82
    [Google Scholar]
  95. 95.
    Castellino P, Luzi L, Simonson DC, Haymond M, DeFronzo RA 1987. Effect of insulin and plasma amino acid concentrations on leucine metabolism in man. Role of substrate availability on estimates of whole body protein synthesis. J. Clin. Investig. 80:61784–93
    [Google Scholar]
  96. 96.
    Holeček M, Šprongl L, Skopec F, Andrýs C, Pecka M 1997. Leucine metabolism in TNF-α and endotoxin-treated rats: contribution of hepatic tissue. Am. J. Physiol. Endocrinol. Metab. 273:6E1052–58
    [Google Scholar]
  97. 97.
    Riis ALD, Jørgensen JOL, Gjedde S, Nørrelund H, Jurik AG et al. 2005. Whole body and forearm substrate metabolism in hyperthyroidism: evidence of increased basal muscle protein breakdown. Am. J. Physiol. Endocrinol. Metab. 288:6E1067–73
    [Google Scholar]
  98. 98.
    Riis ALD, Jørgensen JOL, Ivarsen P, Frystyk J, Weeke J, Møller N 2008. Increased protein turnover and proteolysis is an early and primary feature of short-term experimental hyperthyroidism in healthy women. J. Clin. Endocrinol. Metab. 93:103999–4005
    [Google Scholar]
  99. 99.
    Kobayashi R, Shimomura Y, Otsuka M, Popov KM, Harris RA 2000. Experimental hyperthyroidism causes inactivation of the branched-chain α-ketoacid dehydrogenase complex in rat liver. Arch. Biochem. Biophys. 375:155–61
    [Google Scholar]
  100. 100.
    el-Khoury AE, Forslund A, Olsson R, Branth S, Sjodin A et al. 1997. Moderate exercise at energy balance does not affect 24-h leucine oxidation or nitrogen retention in healthy men. Am. J. Physiol. Endocrinol. Metab. 273:2E394–407
    [Google Scholar]
  101. 101.
    Phillips SM, Atkinson SA, Tarnopolsky MA, MacDougall JD 1993. Gender differences in leucine kinetics and nitrogen balance in endurance athletes. J. Appl. Physiol. 75:52134–41
    [Google Scholar]
  102. 102.
    Wagenmakers AJM, Brookes JH, Coakley JH, Reilly T, Edwards RHT 1989. Exercise-induced activation of the branched-chain 2-oxo acid dehydrogenase in human muscle. Eur. J. Appl. Physiol. Occupat. Physiol. 59:3159–67
    [Google Scholar]
  103. 103.
    White TP, Brooks GA 1981. [U-14C]-glucose, -alanine, and -leucine oxidation in rats at rest and two intensities of running. Am. J. Physiol. Endocrinol. Metab. 240:2E155–65
    [Google Scholar]
  104. 104.
    McKenzie S, Phillips SM, Carter SL, Lowther S, Gibala MJ, Tarnopolsky MA 2000. Endurance exercise training attenuates leucine oxidation and BCOAD activation during exercise in humans. Am. J. Physiol. Endocrinol. Metab. 278:4E580–87
    [Google Scholar]
  105. 105.
    Hamadeh MJ, Devries MC, Tarnopolsky MA 2005. Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise. J. Clin. Endocrinol. Metab. 90:63592–99
    [Google Scholar]
  106. 106.
    Overmyer K, Evans C, Qi N, Minogue C, Carson J et al. 2015. Maximal oxidative capacity during exercise is associated with skeletal muscle fuel selection and dynamic changes in mitochondrial protein acetylation. Cell Metab 21:3468–78
    [Google Scholar]
  107. 107.
    Dohm GL, Hecker AL, Brown WE, Klain GJ, Puente FR et al. 1977. Adaptation of protein metabolism to endurance training. Biochem. J. 164:705–8
    [Google Scholar]
  108. 108.
    Hatazawa Y, Tadaishi M, Nagaike Y, Morita A, Ogawa Y et al. 2014. PGC-1α-mediated branched-chain amino acid metabolism in the skeletal muscle. PLOS ONE 9:3e91006
    [Google Scholar]
  109. 109.
    Hatazawa Y, Senoo N, Tadaishi M, Ogawa Y, Ezaki O et al. 2015. Metabolomic analysis of the skeletal muscle of mice overexpressing PGC-1α. PLOS ONE 10:6e0129084
    [Google Scholar]
  110. 110.
    Neinast MD, Jang C, Hui S, Murashige DS, Chu Q et al. 2018. Quantitative analysis of the whole-body metabolic fate of branched-chain amino acids. Cell Metab In press
  111. 111.
    Hutson S, Wallin R, Hall T 1992. Identification of mitochondrial branched chain aminotransferase and its isoforms in rat tissues. J. Biol. Chem. 267:2215681–86
    [Google Scholar]
  112. 112.
    Ding C, Li Y, Guo F, Jiang Y, Ying W et al. 2016. A cell-type-resolved liver proteome. Mol. Cell. Proteom. 15:103190–202
    [Google Scholar]
  113. 113.
    Palacín M, Estévez R, Bertran J, Zorzano A 1998. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol. Rev. 78:4969–1054
    [Google Scholar]
  114. 114.
    Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H 1998. Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem. 273:3723629–32
    [Google Scholar]
  115. 115.
    Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J et al. 1998. Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395:6699288–91
    [Google Scholar]
  116. 116.
    Oxender DL, Christensen HN 1963. Distinct mediating systems for the transport of neutral amino acids by the Ehrlich cell. J. Biol. Chem. 238:113686–99
    [Google Scholar]
  117. 117.
    Verrey F. 2003. System L: heteromeric exchangers of large, neutral amino acids involved in directional transport. Pflügers Arch 445:5529–33
    [Google Scholar]
  118. 118.
    Newgard CB. 2012. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 15:5606–14
    [Google Scholar]
  119. 119.
    Smith QR, Momma S, Aoyagi M, Rapoport SI 1987. Kinetics of neutral amino acid transport across the blood‐brain barrier. J. Neurochem. 49:51651–58
    [Google Scholar]
  120. 120.
    Gluud LL, Dam G, Les I, Marchesini G, Borre M et al. 2017. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst. Rev. 9:1–83
    [Google Scholar]
  121. 121.
    Silva LS, Poschet G, Nonnenmacher Y, Becker HM, Sapcariu S et al. 2017. Branched‐chain ketoacids secreted by glioblastoma cells via MCT1 modulate macrophage phenotype. EMBO Rep 2017:e201744154
    [Google Scholar]
  122. 122.
    Harper Alfred E. 1989. Chairman's remarks: thoughts on the role of branched‐chain α‐keto acid dehydrogenase complex in nitrogen metabolism. Ann. N.Y. Acad. Sci. 573:1267–73
    [Google Scholar]
  123. 123.
    Nurjhan N, Bucci A, Perriello G, Stumvoll M, Dailey G et al. 1995. Glutamine: a major gluconeogenic precursor and vehicle for interorgan carbon transport in man. J. Clin. Investig. 95:1272–77
    [Google Scholar]
  124. 124.
    Haymond MW, Miles JM 1982. Branched chain amino acids as a major source of alanine nitrogen in man. Diabetes 31:186–89
    [Google Scholar]
  125. 125.
    Odessey R, Khairallah EA, Goldberg AL 1974. Origin and possible significance of alanine production by skeletal muscle. J. Biol. Chem. 249:237623–29
    [Google Scholar]
  126. 126.
    Stumvoll M, Meyer C, Perriello G, Kreider M, Welle S, Gerich J 1998. Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. Am. J. Physiol. Endocrinol. Metab. 274:5E817–26
    [Google Scholar]
  127. 127.
    Sperringer JE, Addington A, Hutson SM 2017. Branched-chain amino acids and brain metabolism. Neurochem. Res. 42:61697–709
    [Google Scholar]
  128. 128.
    Dancis J, Levitz M, Miller S, Westall RG 1959. Maple syrup urine disease. Br. Med. J. 1:511490–91
    [Google Scholar]
  129. 129.
    Menkes JH. 1959. Maple syrup disease: isolation and identification of organic acids in the urine. Pediatrics 23:2348–53
    [Google Scholar]
  130. 130.
    Menkes JH, Hurst PL, Craig JM 1954. A new syndrome: progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 14:5462–67
    [Google Scholar]
  131. 131.
    Schadewaldt P, Bodner-Leidecker A, Hammen H-W, Wendel U 1999. Significance of l-alloisoleucine in plasma for diagnosis of maple syrup urine disease. Clin. Chem. 45:101734–40
    [Google Scholar]
  132. 132.
    Podebrad F, Heil M, Reichert S, Mosandl A, Sewell A, Böhles H 1999. 4,5-Dimethyl-3-hydroxy-2[5H]-furanone (sotolone)—the odour of maple syrup urine disease. J. Inherit. Metab. Dis. 22:2107–14
    [Google Scholar]
  133. 133.
    Sewell AC, Mosandl A, Böhles H 1999. False diagnosis of maple syrup urine disease owing to ingestion of herbal tea. N. Engl. J. Med. 341:10769
    [Google Scholar]
  134. 134.
    Adeva-Andany MM, López-Maside L, Donapetry-García C, Fernández-Fernández C, Sixto-Leal C 2017. Enzymes involved in branched-chain amino acid metabolism in humans. Amino Acids 49:61005–28
    [Google Scholar]
  135. 135.
    Yudkoff M. 1997. Brain metabolism of branched‐chain amino acids. Glia 21:192–98
    [Google Scholar]
  136. 136.
    Yudkoff M, Nissim I, Kim S, Pleasure D, Hummeler K, Segal S 1983. [15N] leucine as a source of [15N] glutamate in organotypic cerebellar explants. Biochem. Biophys. Res. Commun. 115:1174–79
    [Google Scholar]
  137. 137.
    Burrage LC, Nagamani SCS, Campeau PM, Lee BH 2014. Branched-chain amino acid metabolism: from rare Mendelian diseases to more common disorders. Hum. Mol. Genet. 23:R1R1–8
    [Google Scholar]
  138. 138.
    Gambello MJ, Li H 2018. Current strategies for the treatment of inborn errors of metabolism. J. Genet. Genom. 45:261–70
    [Google Scholar]
  139. 139.
    Díaz VM, Camarena C, de la Vega Á, Martínez-Pardo M, Díaz C et al. 2014. Liver transplantation for classical maple syrup urine disease: long-term follow-up. J. Pediatr. Gastroenterol. Nutr. 59:5636–39
    [Google Scholar]
  140. 140.
    Barshop BA, Khanna A 2005. Domino hepatic transplantation in maple syrup urine disease. N. Engl. J. Med. 353:222410–11
    [Google Scholar]
  141. 141.
    García‐Cazorla A, Oyarzabal A, Fort J, Robles C, Castejón E et al. 2014. Two novel mutations in the BCKDK (branched‐chain keto‐acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients. Hum. Mutat. 35:4470–77
    [Google Scholar]
  142. 142.
    Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM et al. 2012. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science 338:6105394–97
    [Google Scholar]
  143. 143.
    Tărlungeanu DC, Deliu E, Dotter CP, Kara M, Janiesch PC et al. 2016. Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder. Cell 167:61481–94.e18
    [Google Scholar]
  144. 144.
    Adibi SA. 1968. Influence of dietary deprivations on plasma concentration of free amino acids of man. J. Appl. Physiol. 25:152–57
    [Google Scholar]
  145. 145.
    Felig P, Marliss E, Cahill GF 1969. Plasma amino acid levels and insulin secretion in obesity. N. Engl. J. Med. 281:15811–16
    [Google Scholar]
  146. 146.
    Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP et al. 2011. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17:4448–53
    [Google Scholar]
  147. 147.
    Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD et al. 2009. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab 9:4311–26
    [Google Scholar]
  148. 148.
    Liu J, Semiz S, van der Lee SJ, van der Spek A, Verhoeven A et al. 2017. Metabolomics based markers predict type 2 diabetes in a 14-year follow-up study. Metabolomics 13:9104
    [Google Scholar]
  149. 149.
    Guasch-Ferré M, Hruby A, Toledo E, Clish CB, Martínez-González MA et al. 2016. Metabolomics in prediabetes and diabetes: a systematic review and meta-analysis. Diabetes Care 39:5833–46
    [Google Scholar]
  150. 150.
    Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J et al. 2016. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis. PLOS Med 13:11e1002179
    [Google Scholar]
  151. 151.
    Harris L-ALS, Smith GI, Patterson BW, Ramaswamy RS, Okunade AL et al. 2017. Alterations in 3-hydroxyisobutyrate and FGF21 metabolism are associated with protein ingestion-induced insulin resistance. Diabetes 66:71871–78
    [Google Scholar]
  152. 152.
    Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD et al. 2017. Restoration of metabolic health by decreased consumption of branched-chain amino acids: a low BCAA diet restores metabolic health. J. Physiol. 596:4623–45
    [Google Scholar]
  153. 153.
    Mahendran Y, Jonsson A, Have CT, Allin KH, Witte DR et al. 2017. Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels. Diabetologia 60:5873–78
    [Google Scholar]
  154. 154.
    Wang Q, Holmes MV, Davey Smith G, Ala-Korpela M 2017. Genetic support for a causal role of insulin resistance on circulating branched-chain amino acids and inflammation. Diabetes Care 40:121779–86
    [Google Scholar]
  155. 155.
    Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB 2010. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J. Biol. Chem. 285:1511348–56
    [Google Scholar]
  156. 156.
    Lips MA, Van Klinken JB, van Harmelen V, Dharuri HK, ’t Hoen PAC et al. 2014. Roux-en-Y gastric bypass surgery, but not calorie restriction, reduces plasma branched-chain amino acids in obese women independent of weight loss or the presence of type 2 diabetes. Diabetes Care 37:123150–56
    [Google Scholar]
  157. 157.
    Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P et al. 2008. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLOS Med 5:3e51
    [Google Scholar]
  158. 158.
    Sears DD, Hsiao G, Hsiao A, Yu JG, Courtney CH et al. 2009. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization. PNAS 106:4418745–50
    [Google Scholar]
  159. 159.
    She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ 2007. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. AJP Endocrinol. Metab. 293:6E1552–63
    [Google Scholar]
  160. 160.
    Wiklund P, Zhang X, Pekkala S, Autio R, Kong L et al. 2016. Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women. Sci. Rep. 6:24540
    [Google Scholar]
  161. 161.
    Burrill JS, Long EK, Reilly B, Deng Y, Armitage IM et al. 2015. Inflammation and ER stress regulate branched-chain amino acid uptake and metabolism in adipocytes. Mol. Endocrinol. 29:3411–20
    [Google Scholar]
  162. 162.
    Lo KA, Labadorf A, Kennedy NJ, Han MS, Yap YS et al. 2013. Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance. Cell Rep 5:1259–70
    [Google Scholar]
  163. 163.
    Hsiao G, Chapman J, Ofrecio JM, Wilkes J, Resnik JL et al. 2011. Multi-tissue, selective PPARγ modulation of insulin sensitivity and metabolic pathways in obese rats. Am. J. Physiol. Endocrinol. Metab. 300:1E164–74
    [Google Scholar]
  164. 164.
    Lian K, Du C, Liu Y, Zhu D, Yan W et al. 2015. Impaired adiponectin signaling contributes to disturbed catabolism of branched-chain amino acids in diabetic mice. Diabetes 64:149–59
    [Google Scholar]
  165. 165.
    White PJ, Lapworth AL, An J, Wang L, McGarrah RW et al. 2016. Branched-chain amino acid restriction in Zucker-fatty rats improves muscle insulin sensitivity by enhancing efficiency of fatty acid oxidation and acyl-glycine export. Mol. Metab. 5:7538–51
    [Google Scholar]
  166. 166.
    White PJ, McGarrah RW, Grimsrud PA, Tso S-C, Yang W-H et al. 2018. The BCKDH kinase and phosphatase integrate BCAA and lipid metabolism via regulation of ATP-citrate lyase. Cell Metab 27:61281–93.e7
    [Google Scholar]
  167. 167.
    DeFronzo RA, Tripathy D 2009. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care 32:Suppl. 2S157–63
    [Google Scholar]
  168. 168.
    Pedroso J, Zampieri T, Donato J 2015. Reviewing the effects of l-leucine supplementation in the regulation of food intake, energy balance, and glucose homeostasis. Nutrients 7:53914–37
    [Google Scholar]
  169. 169.
    Mardinoglu A, Gogg S, Lotta LA, Stancakova A, Nerstedt A et al. 2018. Elevated plasma levels of 3-hydroxyisobutyric acid are associated with incident type 2 diabetes. EBioMedicine 27:151–55
    [Google Scholar]
  170. 170.
    Budhathoki S, Iwasaki M, Yamaji T, Yamamoto H, Kato Y, Tsugane S 2016. Association of plasma concentrations of branched-chain amino acids with risk of colorectal adenoma in a large Japanese population. Ann. Oncol. 28:4818–23
    [Google Scholar]
  171. 171.
    Mayers JR, Wu C, Clish CB, Kraft P, Torrence ME et al. 2014. Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat. Med. 20:101193–98
    [Google Scholar]
  172. 172.
    Nezami Ranjbar MR, Luo Y, Di Poto C, Varghese RS, Ferrarini A et al. 2015. GC-MS based plasma metabolomics for identification of candidate biomarkers for hepatocellular carcinoma in Egyptian cohort. PLOS ONE 10:6e0127299
    [Google Scholar]
  173. 173.
    Watanabe A, Higashi T, Sakata T, Nagashima H 1984. Serum amino acid levels in patients with hepatocellular carcinoma. Cancer 54:91875–82
    [Google Scholar]
  174. 174.
    Mayers JR, Torrence ME, Danai LV, Papagiannakopoulos T, Davidson SM et al. 2016. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras-driven cancers. Science 353:63041161–65
    [Google Scholar]
  175. 175.
    Bi X, Henry CJ 2017. Plasma-free amino acid profiles are predictors of cancer and diabetes development. Nutr. Diabetes 7:3e249
    [Google Scholar]
  176. 176.
    Wei J, Xie G, Zhou Z, Shi P, Qiu Y et al. 2011. Salivary metabolite signatures of oral cancer and leukoplakia. Int. J. Cancer 129:92207–17
    [Google Scholar]
  177. 177.
    Chang IW, Wu WJ, Wang YH, Wu TF, Liang PI et al. 2015. BCAT1 overexpression is an indicator of poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder. Histopathology 68:4520–32
    [Google Scholar]
  178. 178.
    Xu Y, Yu W, Yang T, Zhang M, Liang C et al. 2018. Overexpression of BCAT1 is a prognostic marker in gastric cancer. Hum. Pathol. 75:41–46
    [Google Scholar]
  179. 179.
    Zheng YH, Hu WJ, Chen BC, Grahn THM, Zhao YR et al. 2016. BCAT1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin. Liver Int 36:121836–47
    [Google Scholar]
  180. 180.
    Tönjes M, Barbus S, Park YJ, Wang W, Schlotter M et al. 2013. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19:7901–8
    [Google Scholar]
  181. 181.
    Xu W, Yang H, Liu Y, Yang Y, Wang P et al. 2011. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19:117–30
    [Google Scholar]
  182. 182.
    Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T et al. 2017. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 545:7655500–4
    [Google Scholar]
  183. 183.
    Oktyabri D, Ishimura A, Tange S, Terashima M, Suzuki T 2016. DOT1L histone methyltransferase regulates the expression of BCAT1 and is involved in sphere formation and cell migration of breast cancer cell lines. Biochimie 123:20–31
    [Google Scholar]
  184. 184.
    Eden A, Simchen G, Benvenisty N 1996. Two yeast homologs of ECA39, a target for c-Myc regulation, code for cytosolic and mitochondrial branched-chain amino acid aminotransferases. J. Biol. Chem. 271:3420242–45
    [Google Scholar]
  185. 185.
    Zhou W, Feng X, Ren C, Jiang X, Liu W et al. 2013. Over-expression of BCAT1, a c-Myc target gene, induces cell proliferation, migration and invasion in nasopharyngeal carcinoma. Mol. Cancer 12:153
    [Google Scholar]
  186. 186.
    Raffel S, Falcone M, Kneisel N, Hansson J, Wang W et al. 2017. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551:384–88
    [Google Scholar]
  187. 187.
    McBrayer SK, Mayers JR, DiNatale GJ, Shi DD, Khanal J et al. 2018. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175:1101–16
    [Google Scholar]
  188. 188.
    Zhang L, Han J 2017. Branched-chain amino acid transaminase 1 (BCAT1) promotes the growth of breast cancer cells through improving mTOR-mediated mitochondrial biogenesis and function. Biochem. Biophys. Res. Commun. 486:2224–31
    [Google Scholar]
  189. 189.
    Bhattacharya S, Granger CB, Craig D, Haynes C, Bain J et al. 2014. Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. Atherosclerosis 232:1191–96
    [Google Scholar]
  190. 190.
    Shah SH, Bain JR, Muehlbauer MJ, Stevens RD, Crosslin DR et al. 2010. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ. Cardiovasc. Genet. 3:2207–14
    [Google Scholar]
  191. 191.
    Shah SH, Sun J-L, Stevens RD, Bain JR, Muehlbauer MJ et al. 2012. Baseline metabolomic profiles predict cardiovascular events in patients at risk for coronary artery disease. Am. Heart J. 163:5844–50
    [Google Scholar]
  192. 192.
    McGarrah RW, Crown SB, Zhang G-F, Shah SH, Newgard CB 2018. Cardiovascular metabolomics. Circ. Res. 122:91238–58
    [Google Scholar]
  193. 193.
    Li T, Zhang Z, Kolwicz SC, Abell L, Roe ND et al. 2017. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab 25:2374–85
    [Google Scholar]
  194. 194.
    Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M et al. 2016. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133:212038–49
    [Google Scholar]
  195. 195.
    Wang W, Zhang F, Xia Y, Zhao S, Yan W et al. 2016. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 311:5H1160–69
    [Google Scholar]
  196. 196.
    McNulty PH, Jacob R, Deckelbaum LI, Young LH 2000. Effect of hyperinsulinemia on myocardial amino acid uptake in patients with coronary artery disease. Metab. Clin. Exp. 49:101365–69
    [Google Scholar]
  197. 197.
    Schwartz RG, Barrett EJ, Francis CK, Jacob R, Zaret BL 1985. Regulation of myocardial amino acid balance in the conscious dog. J. Clin. Investig. 75:41204–11
    [Google Scholar]
  198. 198.
    Turer AT, Stevens RD, Bain JR, Muehlbauer MJ, van der Westhuizen J et al. 2009. Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusion. Circulation 119:131736–46
    [Google Scholar]
  199. 199.
    Buse MG, Biggers JF, Friderici KH, Buse JF 1972. Oxidation of branched chain amino acids by isolated hearts and diaphragms of the rat: the effect of fatty acids, glucose, and pyruvate respiration. J. Biol. Chem. 247:248085–96
    [Google Scholar]
  200. 200.
    De Jong KA, Lopaschuk GD 2017. Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Can. J. Cardiol. 33:7860–71
    [Google Scholar]
  201. 201.
    Lopaschuk GD. 2017. Metabolic modulators in heart disease: past, present, and future. Can. J. Cardiol. 33:7838–49
    [Google Scholar]
  202. 202.
    McMullen JR. 2004. Inhibition of mTOR signaling with rapamycin regresses established cardiac hypertrophy induced by pressure overload. Circulation 109:243050–55
    [Google Scholar]
  203. 203.
    Völkers M, Toko H, Doroudgar S, Din S, Quijada P et al. 2013. Pathological hypertrophy amelioration by PRAS40-mediated inhibition of mTORC1. PNAS 110:3112661–66
    [Google Scholar]
  204. 204.
    Sciarretta S, Forte M, Frati G, Sadoshima J 2018. New insights into the role of mTOR signaling in the cardiovascular system. Circ. Res. 122:3489–505
    [Google Scholar]
  205. 205.
    Jackson RH, Singer TP 1983. Inactivation of the 2-ketoglutarate and pyruvate dehydrogenase complexes of beef heart by branched chain keto acids. J. Biol. Chem. 258:31857–65
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-020518-114455
Loading
/content/journals/10.1146/annurev-physiol-020518-114455
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error