The article shows that skeletal muscle plays a dominant role in the catabolism of branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) and the pathogenesis of their decreased concentrations in liver cirrhosis, increased concentrations in diabetes, and nonspecific alterations in disorders with signs of systemic inflammatory response syndrome (SIRS), such as burn injury and sepsis. The main role of skeletal muscle in BCAA catabolism is due to its mass and high activity of BCAA aminotransferase, which is absent in the liver. Decreased BCAA levels in liver cirrhosis are due to increased use of the BCAA as a donor of amino group to alpha-ketoglutarate for synthesis of glutamate, which in muscles acts as a substrate for ammonia detoxification to glutamine. Increased BCAA levels in diabetes are due to alterations in glycolysis, citric acid cycle, and fatty acid oxidation. Decreased glycolysis and citric cycle activity impair BCAA transamination to branched-chain keto acids (BCKAs) due to decreased supply of amino group acceptors (alpha-ketoglutarate, pyruvate, and oxaloacetate); increased fatty acid oxidation inhibits flux of BCKA through BCKA dehydrogenase due to increased supply of NADH and acyl-CoAs. Alterations in BCAA levels in disorders with SIRS are inconsistent due to contradictory effects of SIRS on muscles. Specifically, increased proteolysis and insulin resistance tend to increase BCAA levels, whereas activation of BCKA dehydrogenase and glutamine synthesis tend to decrease BCAA levels. The studies are needed to elucidate the role of alterations in BCAA metabolism and the effects of BCAA supplementation on the outcomes of specific diseases.

Faculty of Medicine in Hradec Králové Charles University Hradec Králové Czech Republic

Zobrazit více v PubMed

ADAM S, ALMEIDA MF, ASSOUN M, BARUTEAU J, BERNABE SM, BIGOT S, CHAMPION H, DALY A, DASSY M, DAWSON S, ET AL. Dietary management of urea cycle disorders: European practice. Mol Genet Metab. 2013;110:439–445. doi: 10.1016/j.ymgme.2013.09.003. PubMed DOI

AFTRING RP, MILLER WJ, BUSE MG. Effects of diabetes and starvation on skeletal muscle branched-chain alpha-keto acid dehydrogenase activity. Am J Physiol. 1988;254:E292–E300. doi: 10.1152/ajpendo.1988.254.3.E292. PubMed DOI

ASKANAZI J, CARPENTIER YA, MICHELSEN CB, ELWYN DH, FURST P, KANTROWITZ LR, GUMP FE, KINNEY JM. Muscle and plasma amino acids following injury. Influence of intercurrent infection. Ann Surg. 1980;192:78–85. doi: 10.1097/00000658-198007000-00014. PubMed DOI PMC

BEATTY CH, WEST ES, BOCEK RM. Effect of succinate, fumarate, and oxalacetate on ketone body production by liver slices from non-diabetic and diabetic rats. J Biol Chem. 1958;230:725–733. doi: 10.1016/S0021-9258(18)70495-X. PubMed DOI

BEUTLER B, CERAMI A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986;320:584–588. doi: 10.1038/320584a0. PubMed DOI

BONEN A, HEYNEN M, HATTA H. Distribution of monocarboxylate transporters MCT1-MCT8 in rat tissues and human skeletal muscle. Appl Physiol Nutr Metab. 2006;31:31–39. doi: 10.1139/h05-002. PubMed DOI

BORGHI L, LUGARI R, MONTANARI A, DALL’ARGINE P, ELIA GF, NICOLOTTI V, SIMONI I, PARMEGGIANI A, NOVARINI A, GNUDI A. Plasma and skeletal muscle free amino acids in type I, insulin-treated diabetic subjects. Diabetes. 1985;34:812–815. doi: 10.2337/diabetes.34.8.812. PubMed DOI

BROSNAN JT, MAN KC, HALL DE, COLBOURNE SA, BROSNAN ME. Interorgan metabolism of amino acids in streptozotocin-diabetic ketoacidotic rat. Am J Physiol. 1983;244:E151–E158. doi: 10.1152/ajpendo.1983.244.2.E151. PubMed DOI

CLEMMESEN JO, KONDRUP J, OTT P. Splanchnic and leg exchange of amino acids and ammonia in acute liver failure. Gastroenterology. 2000;118:1131–1139. doi: 10.1016/S0016-5085(00)70366-0. PubMed DOI

CYNOBER L, DINH FN, BLONDE F, SAIZY R, GIBOUDEAU J. Plasma and urinary amino acid pattern in severe burn patients-evolution throughout the healing period. Am J Clin Nutr. 1982;36:416–425. doi: 10.1093/ajcn/36.3.416. PubMed DOI

DAVULURI G, ALLAWY A, THAPALIYA S, RENNISON JH, SINGH D, KUMAR A, SANDLERS Y, Van WAGONER DR, FLASK CA, HOPPEL C, KASUMOV T, DASARATHY S. Hyperammonaemia-induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress. J Physiol. 2016;594:7341–7360. doi: 10.1113/JP272796. PubMed DOI PMC

DAVULURI G, KROKOWSKI D, GUAN BJ, KUMAR A, THAPALIYA S, SINGH D, HATZOGLOU M, DASARATHY S. Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis. J Hepatol. 2016;65:929–937. doi: 10.1016/j.jhep.2016.06.004. PubMed DOI PMC

De BANDT JP, CYNOBER L. Therapeutic use of branched-chain amino acids in burn, trauma, and sepsis. J Nutr. 2006;136:308S–313S. doi: 10.1093/jn/136.1.308S. PubMed DOI

DEFRONZO RA, GUNNARSSON R, BJÖRKMAN O, OLSSON M, WAHREN J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76:149–155. doi: 10.1172/JCI111938. PubMed DOI PMC

DRUML W, HEINZEL G, KLEINBERGER G. Amino acid kinetics in patients with sepsis. Am J Clin Nutr. 2001;73:908–913. doi: 10.1093/ajcn/73.5.908. PubMed DOI

DURSCHLAG RP, SMITH RJ. Regulation of glutamine production by skeletal muscle cells in culture. Am J Physiol. 1985;248:C442–C448. doi: 10.1152/ajpcell.1985.248.5.C442. PubMed DOI

FELIG P. Amino acid metabolism in man. Annu Rev Biochem. 1975;44:933–955. doi: 10.1146/annurev.bi.44.070175.004441. PubMed DOI

FISCHER JE, FUNOVICS JM, AGUIRRE A, JAMES JH, KEANE JM, WESDORP RI, YOSHIMURA N, WESTMAN T. The role of plasma amino acids in hepatic encephalopathy. Surgery. 1975;78:276–290. PubMed

GELFAND RA, GLICKMAN MG, JACOB R, SHERWIN RS, DEFRONZO RA. Removal of infused amino acids by splanchnic and leg tissues in humans. Am J Physiol. 1986;250:E407–E413. doi: 10.1152/ajpendo.1986.250.4.E407. PubMed DOI

GIRARD G, BUTTERWORTH RF. Effect of portacaval anastomosis on glutamine synthetase activities in liver, brain, and skeletal muscle. Dig Dis Sci. 1992;37:1121–1126. doi: 10.1007/BF01300297. PubMed DOI

HARDY G, HARDY IJ. Can glutamine enable the critically ill to cope better with infection? JPEN J Parenter Enteral Nutr. 2008;32:489–491. doi: 10.1177/0148607108319796. PubMed DOI

HARPER AE, MILLER RH, BLOCK KP. Branched-chain amino acid metabolism. Ann Rev Nutr. 1984;4:409–454. doi: 10.1146/annurev.nu.04.070184.002205. PubMed DOI

HARRIS RA, JOSHI M, JEOUNG NH. Mechanisms responsible for regulation of branched-chain amino acid catabolism. Biochem Biophys Res Commun. 2004;313:391–396. doi: 10.1016/j.bbrc.2003.11.007. PubMed DOI

HARRIS RA, JOSHI M, JEOUNG NH, OBAYASHI M. Overview of the molecular and biochemical basis of branched-chain amino acid catabolism. J Nutr. 2005;135:1527S–1530S. doi: 10.1093/jn/135.6.1527S. PubMed DOI

HAYASHI M, IKEZAWA K, ONO A, OKABAYASHI S, HAYASHI Y, SHIMIZU S, MIZUNO T, MAEDA K, AKASAKA T, NAITO M, MICHIDA T, UESHIMA D, NADA T, KAWAGUCHI K, NAKAMURA T, KATAYAMA K. Evaluation of the effects of combination therapy with branched-chain amino acid and zinc supplements on nitrogen metabolism in liver cirrhosis. Hepatol Res. 2007;37:615–619. doi: 10.1111/j.1872-034X.2007.00095.x. PubMed DOI

HE FL, QI RZ, ZHANG YN, ZHANG K, ZHU-GE YZ, WANG M, WANG Y, JIA JD, LIU FQ. Transjugular intrahepatic portosystemic shunt and splenectomy are more effective than endoscopic therapy for recurrent variceal bleeding in patients with idiopathic noncirrhotic portal hypertension. World J Clin Cases. 2020;8:1871–1877. doi: 10.12998/wjcc.v8.i10.1871. PubMed DOI PMC

HIROSE T, SHIMIZU K, OGURA H, TASAKI O, HAMASAKI T, YAMANO S, OHNISHI M, KUWAGATA Y, SHIMAZU T. Altered balance of the aminogram in patients with sepsis - the relation to mortality. Clin Nutr. 2014;33:179–182. doi: 10.1016/j.clnu.2013.11.017. PubMed DOI

HOLECEK M. Leucine metabolism in fasted and tumor necrosis factor-treated rats. Clin Nutr. 1996;15:91–93. doi: 10.1016/S0261-5614(96)80028-8. PubMed DOI

HOLECEK M, TILSER I, SKOPEC F, SPRONGL L. Leucine metabolism in rats with cirrhosis. J Hepatol. 1996;24:209–216. doi: 10.1016/S0168-8278(96)80031-6. PubMed DOI

HOLEČEK M, MRÁZ J, TILŠER I. Plasma amino acids in four models of experimental liver injury in rats. Amino Acids. 1996;10:229–241. doi: 10.1007/BF00807325. PubMed DOI

HOLECEK M, SPRONGL L, SKOPEC F, ANDRÝS C, PECKA M. Leucine metabolism in TNF-alpha- and endotoxin-treated rats: contribution of hepatic tissue. Am J Physiol. 1997;273:E1052–E1058. doi: 10.1152/ajpendo.1997.273.6.E1052. PubMed DOI

HOLECEK M. Nutritional modulation of liver regeneration by carbohydrates, lipids, and amino acids: a review. Nutrition. 1999;15:784–788. doi: 10.1016/S0899-9007(99)00158-6. PubMed DOI

HOLECEK M, SKALSKÁ H, MRÁZ J. Plasma amino acid levels after carbon tetrachloride induced acute liver damage. A dose-response and time-response study in rats. Amino Acids. 1999;16:1–11. doi: 10.1007/BF01318880. PubMed DOI

HOLECEK M, SPRONGL L, TICHÝ M. Effect of hyperammonemia on leucine and protein metabolism in rats. Metabolism. 2000;49:1330–1334. doi: 10.1053/meta.2000.9531. PubMed DOI

HOLECEK M, KANDAR R, SISPERA L, KOVARIK M. Acute hyperammonemia activates branched-chain amino acid catabolism and decreases their extracellular concentrations: different sensitivity of red and white muscle. Amino Acids. 2011;40:575–584. doi: 10.1007/s00726-010-0679-z. PubMed DOI

HOLECEK M. Evidence of a vicious cycle in glutamine synthesis and breakdown in pathogenesis of hepatic encephalopathy-therapeutic perspectives. Metab Brain Dis. 2014;29:9–17. doi: 10.1007/s11011-013-9428-9. PubMed DOI PMC

HOLECEK M, SIMAN P, VODENICAROVOVA M, KANDAR R. Alterations in protein and amino acid metabolism in rats fed a branched-chain amino acid- or leucine-enriched diet during postprandial and postabsorptive states. Nutr Metab (Lond) 2016;13:12. doi: 10.1186/s12986-016-0072-3. PubMed DOI PMC

HOLEČEK M, MIČUDA S. Amino acid concentrations and protein metabolism of two types of rat skeletal muscle in postprandial state and after brief starvation. Physiol Res. 2017;66:959–967. doi: 10.33549/physiolres.933638. PubMed DOI

HOLECEK M, VODENICAROVOVA M, SIMAN P. Acute effects of phenylbutyrate on glutamine, branched-chain amino acid and protein metabolism in skeletal muscles of rats. Int J Exp Pathol. 2017;98:127–133. doi: 10.1111/iep.12231. PubMed DOI PMC

HOLEČEK M, VODENIČAROVOVÁ M. Effects of branched-chain amino acids on muscles under hyperammonemic conditions. J Physiol Biochem. 2018;74:523–530. doi: 10.1007/s13105-018-0646-9. PubMed DOI

HOLEČEK M, VODENIČAROVOVÁ M. Muscle wasting and branched-chain amino acid, alpha-ketoglutarate, and ATP depletion in a rat model of liver cirrhosis. Int J Exp Pathol. 2018;99:274–281. doi: 10.1111/iep.12299. PubMed DOI PMC

HOLEČEK M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab (Lond) 2018;15:33. doi: 10.1186/s12986-018-0271-1. PubMed DOI PMC

HOLEČEK M. Influence of histidine administration on ammonia and amino acid metabolism: A review. Physiol Res. 2020;69:555–564. doi: 10.33549/physiolres.934449. PubMed DOI PMC

HOLEČEK M, VODENIČAROVOVÁ M. Effects of low and high doses of fenofibrate on protein, amino acid, and energy metabolism in rat. Int J Exp Pathol. 2020;101:171–182. doi: 10.1111/iep.12368. PubMed DOI PMC

HOLEČEK M, VODENIČAROVOVÁ M, FINGROVÁ R. Dual effects of beta-hydroxy-beta-methylbutyrate (HMB) on amino acid, energy, and protein metabolism in the liver and muscles of rats with streptozotocin-induced type 1 diabetes. Biomolecules. 2020;10:E1475. doi: 10.3390/biom10111475. PubMed DOI PMC

HOLEČEK M. Why are branched-chain amino acids increased in starvation and diabetes? Nutrients. 2020;12:3087. doi: 10.3390/nu12103087. PubMed DOI PMC

HUTSON SM, HARPER AE. Blood and tissue branched-chain amino and alpha-keto acid concentrations: effect of diet, starvation, and disease. Am J Clin Nutr. 1981;34:173–183. doi: 10.1093/ajcn/34.2.173. PubMed DOI

JAYAKUMAR AR, NORENBERG MD. Glutamine synthetase: Role in neurological disorders. Adv Neurobiol. 2016;13:327–350. doi: 10.1007/978-3-319-45096-4_13. PubMed DOI

JENSEN-WAERN M, ANDERSSON M, KRUSE R, NILSSON B, LARSSON R, KORSGREN O, ESSÉN-GUSTAVSSON B. Effects of streptozotocin-induced diabetes in domestic pigs with focus on the amino acid metabolism. Lab Anim. 2009;43:249–254. doi: 10.1258/la.2008.008069. PubMed DOI

KAUKONEN KM, BAILEY M, PILCHER D, COOPER DJ, BELLOMO R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372:1629–1638. doi: 10.1056/NEJMoa1415236. PubMed DOI

KELLER U, TURKALJ I, LAAGER R, BLOESCH D, BILZ S. Effects of medium- and long-chain fatty acids on whole body leucine and glucose kinetics in man. Metabolism. 2002;51:754–760. doi: 10.1053/meta.2002.32806. PubMed DOI

LEWELING H, BREITKREUTZ R, BEHNE F, STAEDT U, STRIEBEL JP, HOLM E. Hyperammonemia-induced depletion of glutamate and branched-chain amino acids in muscle and plasma. J Hepatol. 1996;25:756–762. doi: 10.1016/S0168-8278(96)80249-2. PubMed DOI

LIU Z, YIN P, AMATHIEU R, SAVARIN P, XU G. Application of LC-MS-based metabolomics method in differentiating septic survivors from non-survivors. Anal Bioanal Chem. 2016;408:7641–7649. doi: 10.1007/s00216-016-9845-9. PubMed DOI

MAESTRI NE, McGOWAN KD, BRUSILOW SW. Plasma glutamine concentration: a guide in the management of urea cycle disorders. J Pediatr. 1992;121:259–261. doi: 10.1016/S0022-3476(05)81200-4. PubMed DOI

MARCHESINI G, BIANCHI G, MERLI M, AMODIO P, PANELLA C, LOGUERCIO C, ROSSI FANELLI F, ABBIATI R ITALIAN BCAA STUDY GROUP. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124:1792–1801. doi: 10.1016/S0016-5085(03)00323-8. PubMed DOI

MASCARENHAS R, MOBARHAN S. New support for branched-chain amino acid supplementation in advanced hepatic failure. Nutr Rev. 2004;62:33–38. doi: 10.1301/nr.2004.jan.33-38. PubMed DOI

MATTICK JSA, KAMISOGLU K, IERAPETRITOU MG, ANDROULAKIS IP, BERTHIAUME F. Branched-chain amino acid supplementation: impact on signaling and relevance to critical illness. Wiley Interdiscip Rev Syst Biol Med. 2013;5:449–460. doi: 10.1002/wsbm.1219. PubMed DOI PMC

MAVROTHALASSITIS G, TZIMAGIORGIS G, MITSIALIS A, ZANNIS V, PLAITAKIS A, PAPAMATHEAKIS J, MOSCHONAS N. Isolation and characterization of cDNA clones encoding human liver glutamate dehydrogenase: evidence for a small gene family. Proc Natl Acad Sci U S A. 1988;85:3494–3498. doi: 10.1073/pnas.85.10.3494. PubMed DOI PMC

MEIER C, RISTIC Z, KLAUSER S, VERREY F. Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J. 2002;21:580–589. doi: 10.1093/emboj/21.4.580. PubMed DOI PMC

MIERZCHALA-PASIERB M, LIPINSKA-GEDIGA M, FLESZAR MG, LESNIK P, PLACZKOWSKA S, SEREK P, WISNIEWSKI J, GAMIAN A, KRZYSTEK-KORPACKA M. Altered profiles of serum amino acids in patients with sepsis and septic shock - Preliminary findings. Arch Biochem Biophys. 2020;691:108508. doi: 10.1016/j.abb.2020.108508. PubMed DOI

MÖLLER P, BERGSTRÖM J, FÜRST P, HELLSTRÖM K. Muscle biopsy studies in patients with moderate liver cirrhosis with special reference to energy-rich phosphagens and electrolytes. Scand J Gastroenterol. 1984;19:267–272. doi: 10.1080/00365521.1984.12005719. PubMed DOI

NAKAYA Y, OKITA K, SUZUKI K, MORIWAKI H, KATO A, MIWA Y, SHIRAISHI K, OKUDA H, ONJI M, KANAZAWA H, TSUBOUCHI H, KATO S, KAITO M, WATANABE A, HABU D, ITO S, ISHIKAWA T, KAWAMURA N, ARAKAWA Y HEPATIC NUTRITIONAL THERAPY (HNT) STUDY GROUP. BCAA-enriched snack improves nutritional state of cirrhosis. Nutrition. 2007;23:113–120. doi: 10.1016/j.nut.2006.10.008. PubMed DOI

NAWABI MD, BLOCK KP, CHAKRABARTI MC, BUSE MG. Administration of endotoxin, tumor necrosis factor, or interleukin 1 to rats activates skeletal muscle branched-chain alpha-keto acid dehydrogenase. J Clin Invest. 1990;85:256–263. doi: 10.1172/JCI114421. PubMed DOI PMC

NEWGARD CB. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 2012;15:606–614. doi: 10.1016/j.cmet.2012.01.024. PubMed DOI PMC

OKADA A, MORI S, TOTSUKA M, OKAMOTO K, USUI S, FUJITA H, ITAKURA T, MIZOTE H. Branched-chain amino acids metabolic support in surgical patients: a randomized, controlled trial in patients with subtotal or total gastrectomy in 16 Japanese institutions. JPEN J Parenter Enteral Nutr. 1988;12:332–337. doi: 10.1177/0148607188012004332. PubMed DOI

PACY PJ, CHENG KN, FORD GC, HALLIDAY D. Influence of glucagon on protein and leucine metabolism: a study in fasting man with induced insulin resistance. Br J Surg. 1990;77:791–794. doi: 10.1002/bjs.1800770723. PubMed DOI

RANGEL-FRAUSTO MS, PITTET D, COSTIGAN M, HWANG T, DAVIS CS, WENZEL RP. The natural history of the systemic inflammatory response syndrome (SIRS): A prospective study. JAMA. 1995;273:117–123. doi: 10.1001/jama.273.2.117. PubMed DOI

RODNEY S, BONEH A. Amino acid profiles in patients with urea cycle disorders at admission to hospital due to metabolic decompensation. JIMD Rep. 2013;9:97–104. doi: 10.1007/8904_2012_186. PubMed DOI PMC

RODRÍGUEZ T, ALVAREZ B, BUSQUETS S, CARBÓ N, LÓPEZ-SORIANO FJ, ARGILÉS JM. The increased skeletal muscle protein turnover of the streptozotocin diabetic rat is associated with high concentrations of branched-chain amino acids. Biochem Mol Med. 1997;61:87–94. doi: 10.1006/bmme.1997.2585. PubMed DOI

ROSEN HM, YOSHIMURA N, HODGMAN JM, FISCHER JE. Plasma amino acid patterns in hepatic encephalopathy of differing etiology. Gastroenterology. 1977;72:483–487. doi: 10.1016/S0016-5085(77)80261-8. PubMed DOI

RUDERMAN NB, BERGER M. The formation of glutamine and alanine in skeletal muscle. J Biol Chem. 1974;249:5500–5506. doi: 10.1016/S0021-9258(20)79756-5. PubMed DOI

RYAN NT. Metabolic adaptations for energy production during trauma and sepsis. Surg Clin North Am. 1976;56:1073–1090. doi: 10.1016/S0039-6109(16)41032-7. PubMed DOI

SANDSTEDT S, JORFELDT L, LARSSON J. Randomized, controlled study evaluating effects of branched chain amino acids and alpha-ketoisocaproate on protein metabolism after surgery. Br J Surg. 1992;79:217–220. doi: 10.1002/bjs.1800790308. PubMed DOI

SCAGLIA F, CARTER S, O’BRIEN WE, LEE B. Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients. Mol Genet Metab. 2004;81:S79–S85. doi: 10.1016/j.ymgme.2003.11.017. PubMed DOI

SCHOLTEN DJ, MORGAN RE, DAVIS AT, ALBRECHT RM. Failure of BCAA supplementation to promote nitrogen retention in injured patients. J Am Coll Nutr. 1990;9:101–106. doi: 10.1080/07315724.1990.10720357. PubMed DOI

SHAH SH, CROSSLIN DR, HAYNES CS, NELSON S, TURER CB, STEVENS RD, MUEHLBAUER MJ, WENNER BR, BAIN JR, LAFERRÈRE B, GORROOCHURN P, TEIXEIRA J, BRANTLEY PJ, STEVENS VJ, HOLLIS JF, APPEL LJ, LIEN LF, BATCH B, NEWGARD CB, SVETKEY LP. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia. 2012;55:321–330. doi: 10.1007/s00125-011-2356-5. PubMed DOI PMC

SHE P, OLSON KC, KADOTA Y, INUKAI A, SHIMOMURA Y, HOPPEL CL, ADAMS SH, KAWAMATA Y, MATSUMOTO H, SAKAI R, LANG CH, LYNCH CJ. Leucine and protein metabolism in obese Zucker rats. PLoS One. 2013;8:e59443. doi: 10.1371/journal.pone.0059443. PubMed DOI PMC

SHI ZQ, CHANG TM. Amino acid disturbances in experimental hepatic coma rats. Int J Artif Organs. 1984;7:197–202. doi: 10.1177/039139888400700409. PubMed DOI

SHIMOMURA Y, HONDA T, SHIRAKI M, MURAKAMI T, SATO J, KOBAYASHI H, MAWATARI K, OBAYASHI M, HARRIS RA. Branched-chain amino acid catabolism in exercise and liver disease. J Nutr. 2006;136:250S–253S. doi: 10.1093/jn/136.1.250S. PubMed DOI

SHIMOMURA Y, OBAYASHI M, MURAKAMI T, HARRIS RA. Regulation of branched-chain amino acid catabolism: nutritional and hormonal regulation of activity and expression of the branched-chain alpha-keto acid dehydrogenase kinase. Curr Opin Clin Nutr Metab Care. 2001;4:419–423. doi: 10.1097/00075197-200109000-00013. PubMed DOI

SMITH RJ, LARSON S, STRED SE, DURSCHLAG RP. Regulation of glutamine synthetase and glutaminase activities in cultured skeletal muscle cells. J Cell Physiol. 1984;120:197–203. doi: 10.1002/jcp.1041200213. PubMed DOI

SOUBA WW, HERSKOWITZ K, SALLOUM RM, CHEN MK, AUSTGEN TR. Gut glutamine metabolism. JPEN J Parenter Enteral Nutr. 1990;14(Suppl 4):45S–50S. doi: 10.1177/014860719001400403. PubMed DOI

SPYDEVOLD S, DAVIS EJ, BREMER J. Replenishment and depletion of citric acid cycle intermediates in skeletal muscle. Indication of pyruvate carboxylation. Eur J Biochem. 1976;71:155–165. doi: 10.1111/j.1432-1033.1976.tb11101.x. PubMed DOI

SU L, LI H, XIE A, LIU D, RAO W, LAN L, LI X, LI F, XIAO K, WANG H, YAN P, LI X, XIE L. Dynamic changes in amino acid concentration profiles in patients with sepsis. PLoS One. 2015;10:e0121933. doi: 10.1371/journal.pone.0121933. PubMed DOI PMC

SURYAWAN A, HAWES JW, HARRIS RA, SHIMOMURA Y, JENKINS AE, HUTSON SM. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr. 1998;68:72–81. doi: 10.1093/ajcn/68.1.72. PubMed DOI

TEASLEY KM, BUSS RL. Do parenteral nutrition solutions with high concentrations of branched-chain amino acids offer significant benefits to stressed patients? DICP. 1989;23:411–416. doi: 10.1177/106002808902300510. PubMed DOI

TIETZE IN, SØRENSEN SS, EISKJAER H, THOMSEN K, PEDERSEN EB. Tubular handling of amino acids after intravenous infusion of amino acids in healthy humans. Nephrol Dial Transplant. 1992;7:493–500. PubMed

TISCHLER ME, FAGAN JM. Response to trauma of protein, amino acid, and carbohydrate metabolism in injured and uninjured rat skeletal muscles. Metabolism. 1983;32:853–868. doi: 10.1016/0026-0495(83)90198-1. PubMed DOI

URATA Y, OKITA K, KORENAGA K, UCHIDA K, YAMASAKI T, SAKAIDA I. The effect of supplementation with branched-chain amino acids in patients with liver cirrhosis. Hepatol Res. 2007;37:510–516. doi: 10.1111/j.1872-034X.2007.00081.x. PubMed DOI

VENTE JP, Von MEYENFELDT MF, Van EIJK HM, Van BERLO CL, GOUMA DJ, Van der LINDEN CJ, SOETERS PB. Plasma-amino acid profiles in sepsis and stress. Ann Surg. 1989;209:57–62. doi: 10.1097/00000658-198901000-00009. PubMed DOI PMC

VENTE JP, SOETERS PB, Von MEYENFELDT MF, ROUFLART MM, Van der LINDEN CJ, GOUMA DJ. Prospective randomized double-blind trial of branched chain amino acid enriched versus standard parenteral nutrition solutions in traumatized and septic patients. World J Surg. 1991;15:128–133. doi: 10.1007/BF01658984. PubMed DOI

WIJEKOON EP, SKINNER C, BROSNAN ME, BROSNAN JT. Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. Can J Physiol Pharmacol. 2004;82:506–514. doi: 10.1139/y04-067. PubMed DOI

YANG Q, BIRKHAHN RH. Branched-chain transaminase and keto acid dehydrogenase activities in burned rats: evidence for a differential adaptation according to sex. Nutrition. 1997;13:640–645. doi: 10.1016/S0899-9007(97)83006-7. PubMed DOI

ZIMMERMAN T, HORBER F, RODRIGUEZ N, SCHWENK WF, HAYMOND MW. Contribution of insulin resistance to catabolic effect of prednisone on leucine metabolism in humans. Diabetes. 1989;38:1238–1244. doi: 10.2337/diabetes.38.10.1238. PubMed DOI

Origin and Roles of Alanine and Glutamine in Gluconeogenesis in the Liver, Kidneys, and Small Intestine under Physiological and Pathological Conditions

Aspartic Acid in Health and Disease

Role of Impaired Glycolysis in Perturbations of Amino Acid Metabolism in Diabetes Mellitus

Ellagic acid attenuates muscle atrophy in STZ-induced diabetic mice

Muscle Amino Acid and Adenine Nucleotide Metabolism during Exercise and in Liver Cirrhosis: Speculations on How to Reduce the Harmful Effects of Ammonia

Side effects of amino acid supplements