In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, the catabolism of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) is activated and BCAA concentrations decrease. In these conditions, BCAAs are recommended to improve mental functions, protein balance, and muscle performance. However, clinical trials have not demonstrated significant benefits of BCAA-containing supplements. It is hypothesized that, under hyperammonemic conditions, enhanced glutamine availability and decreased BCAA levels facilitate the amination of branched-chain keto acids (BCKAs; α-ketoisocaproate, α-keto-β-methylvalerate, and α-ketoisovalerate) to the corresponding BCAAs, and that BCKA supplementation may offer advantages over BCAAs. Studies examining the effects of ketoanalogues of amino acids have provided proof that subjects with hyperammonemia can effectively synthesize BCAAs from BCKAs. Unfortunately, the benefits of BCKA administration have not been clearly confirmed. The shortcoming of most reports is the use of mixtures intended for patients with renal insufficiency, which might be detrimental for patients with liver injury. It is concluded that (i) BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance and (ii) studies specifically investigating the effects of BCKA, without the interference of other ketoanalogues, are needed to complete the information essential for decisions regarding their suitability in hyperammonemic conditions.

Department of Physiology Charles University Faculty of Medicine in Hradec Králové 500 03 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Banister E.W., Cameron B.J. Exercise-induced hyperammonemia: Peripheral and central effects. Int. J. Sports Med. 1990;11:S129–S142. doi: 10.1055/s-2007-1024864. PubMed DOI

Wilkinson D.J., Smeeton N.J., Watt P.W. Ammonia metabolism, the brain and fatigue; revisiting the link. Prog. Neurobiol. 2010;91:200–219. doi: 10.1016/j.pneurobio.2010.01.012. PubMed DOI

Graham T.E., MacLean D.A. Ammonia and amino acid metabolism in human skeletal muscle during exercise. Can. J. Physiol. Pharmacol. 1992;70:132–141. doi: 10.1139/y92-020. PubMed DOI

Leweling H., Breitkreutz R., Behne F., Staedt U., Striebel J.P., 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

Holeček M., Šprongl 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

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

Fischer J.E., Baldessarini R.J. False neurotransmitters and hepatic failure. Lancet. 1971;298:75–80. doi: 10.1016/S0140-6736(71)92048-4. PubMed DOI

Herlong H.F., Maddrey W.C., Walser M. The use of ornithine salts of branched-chain ketoacids in portal-systemic encephalopathy. Ann. Intern. Med. 1980;93:545–550. doi: 10.7326/0003-4819-93-4-545. 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

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

Batshaw M.L., Brusilow S., Walser M. Long-term management of a case of carbamyl phosphate synthetase deficiency using ketanalogues and hydroxyanalogues of essential amino acids. Pediatrics. 1976;58:227–235. PubMed

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. PubMed PMC

Als-Nielsen B., Koretz R.L., Kjaergard L.L., Gluud C. Branched-chain amino acids for hepatic encephalopathy. Cochrane Database Syst. Rev. 2003 doi: 10.1002/14651858.CD001939. PubMed DOI

Gluud L.L., Dam G., Les I., Córdoba J., Marchesini G., Borre M., Aagaard N.K., Vilstrup H. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst. Rev. 2015 doi: 10.1002/14651858.CD001939.pub2. PubMed DOI

Wolfe R.R., Goodenough R.D., Wolfe M.H., Royle G.T., Nadel E.R. Isotopic analysis of leucine and urea metabolism in exercising humans. J. Appl. Physiol. Respir. Environ. Exerc. Physiol. 1982;52:458–466. doi: 10.1152/jappl.1982.52.2.458. PubMed DOI

Knapik J., Meredith C., Jones B., Fielding R., Young V., Evans W. Leucine metabolism during fasting and exercise. J. Appl. Physiol. (1985) 1991;70:43–47. doi: 10.1152/jappl.1991.70.1.43. PubMed DOI

Bassini A., Magalhães-Neto A.M., Sweet E., Bottino A., Veiga C., Tozzi M.B., Pickard M.B., Cameron L.-C. Caffeine decreases systemic urea in elite soccer players during intermittent exercise. Med. Sci. Sports Exerc. 2013;45:683–690. doi: 10.1249/MSS.0b013e3182797637. PubMed DOI

De Palo E.F., Gatti R., Bigon L., Previti O., De Palo C.B. Branched-chainα-amino acid chronic treatment: Responses of plasma α-keto-related compounds and ammonia when used in physical exercise performance. Amino Acids. 1996;10:317–332. doi: 10.1007/BF00805860. PubMed DOI

Madsen K., MacLean D.A., Kiens B., Christensen D. Effects of glucose, glucose plus branched-chain amino acids, or placebo on bike performance over 100 km. J. Appl. Physiol. (1985) 1996;81:2644–2650. doi: 10.1152/jappl.1996.81.6.2644. PubMed DOI

MacLean D.A., Graham T.E., Saltin B. Stimulation of muscle ammonia production during exercise following branched-chain amino acid supplementation in humans. J. Physiol. 1996;493:909–922. doi: 10.1113/jphysiol.1996.sp021433. PubMed DOI PMC

Watson P., Shirreffs S.M., Maughan R.J. The effect of acute branched-chain amino acid supplementation on prolonged exercise capacity in a warm environment. Eur. J. Appl. Physiol. 2004;93:306–314. doi: 10.1007/s00421-004-1206-2. PubMed DOI

Falavigna G., de Araújo A.J., Rogero M.M., Pires I.S., Pedrosa R.G., Martins E., de Castro I.A., Tirapegui J. Effects of diets supplemented with branched-chain amino acids on the performance and fatigue mechanisms of rats submitted to prolonged physical exercise. Nutrients. 2012;4:1767–1780. doi: 10.3390/nu4111767. PubMed DOI PMC

Wagenmakers A.J., Coakley J.H., Edwards R.H. Metabolism of branched-chain amino acids and ammonia during exercise: Clues from McArdle’s disease. Int. J. Sports Med. 1990;11:S101–S113. doi: 10.1055/s-2007-1024861. 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

Holeček M. Branched-chain amino acid supplementation in treatment of liver cirrhosis: Updated views on how to attenuate their harmful effects on cataplerosis and ammonia formation. Nutrition. 2017;41:80–85. doi: 10.1016/j.nut.2017.04.003. PubMed DOI

Watanabe A., Shiota T., Okita M., Nagashima H. Effect of a branched chain amino acid-enriched nutritional product on the pathophysiology of the liver and nutritional state of patients with liver cirrhosis. Acta Med. Okayama. 1983;37:321–333. PubMed

Nishikawa Y., Ukida M., Matsuo R., Morimoto Y., Omori N., Mikami M., Tsuji T. Administration of a branched-chain amino acid preparation during hepatic failure: A study emphasizing ammonia metabolism. Acta Med. Okayama. 1994;48:25–30. PubMed

Dam G., Keiding S., Munk O.L., Ott P., Buhl M., Vilstrup H., Bak L.K., Waagepetersen H.S., Schousboe A., Møller N., et al. Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects. Am. J. Physiol. 2011;301:G269–G277. doi: 10.1152/ajpgi.00062.2011. PubMed DOI

Meyer H.P., Chamuleau R.A., Legemate D.A., Mol J.A., Rothuizen J. Effects of a branched-chain amino acid-enriched diet on chronic hepatic encephalopathy in dogs. Metab. Brain Dis. 1999;14:103–115. doi: 10.1023/A:1020757730386. PubMed DOI

Jungers P., Chauveau P. Amino acids and keto acids in the treatment of chronic renal failure. Blood Purif. 1988;6:299–314. doi: 10.1159/000169557. PubMed DOI

Walser M., Mitch W.E., Abras E. Supplements containing amino acids and keto acids in the treatment of chronic uremia. Kidney Int. Suppl. 1983;16:S285–S289. PubMed

Teplan V., Schück O., Horácková M., Skibová J., Holecek M. Effect of a keto acid-amino acid supplement on the metabolism and renal elimination of branched-chain amino acids in patients with chronic renal insufficiency on a low protein diet. Wien. Klin. Wochenschr. 2000;112:876–881. PubMed

Harper A.E., Miller R.H., Block K.P. Branched-chain amino acid metabolism. Annu. Rev. Nutr. 1984;4:409–454. doi: 10.1146/annurev.nu.04.070184.002205. PubMed DOI

Imura K., Shiota T., Swain L.M., Walser M. Utilization for protein synthesis of 2-ketoisocaproate relative to utilization of leucine, as estimated from exhalation of labelled CO2. Clin. Sci. (Lond.) 1988;75:301–307. doi: 10.1042/cs0750301. PubMed DOI

Yagi M., Matthews D.E., Walser M. Nitrogen sparing by 2-ketoisocaproate in parenterally fed rats. Am. J. Physiol. 1990;259:E633–E638. doi: 10.1152/ajpendo.1990.259.5.E633. PubMed DOI

Holecek M., Sprongl L., Tilser I. Metabolism of branched-chain amino acids in starved rats: The role of hepatic tissue. Physiol. Res. 2001;50:25–33. PubMed

Holecek M. The BCAA-BCKA cycle: Its relation to alanine and glutamine synthesis and protein balance. Nutrition. 2001;17:70. doi: 10.1016/S0899-9007(00)00483-4. PubMed DOI

Holecek M., Rysava R., Safranek R., Kadlcikova J., Sprongl L. Acute effects of decreased glutamine supply on protein and amino acid metabolism in hepatic tissue: A study using isolated perfused rat liver. Metabolism. 2003;52:1062–1067. doi: 10.1016/S0026-0495(03)00107-0. PubMed DOI

Muñoz S., Walser M. Effect of experimental liver disease on the utilization for protein synthesis of orally administered alpha-ketoisocaproate. Hepatology. 1986;6:472–476. doi: 10.1002/hep.1840060325. PubMed DOI

Walser M., Lund P., Ruderman N.B., Coulter A.W. Synthesis of essential amino acids from their alpha-keto analogues by perfused rat liver and muscle. J. Clin. Invest. 1973;52:2865–2877. doi: 10.1172/JCI107483. PubMed DOI PMC

Brand K. Metabolism of 2-oxoacid analogues of leucine, valine and phenylalanine by heart muscle, brain and kidney of the rat. Biochim. Biophys. Acta. 1981;677:126–132. doi: 10.1016/0304-4165(81)90153-7. PubMed DOI

Holecek M., Sprongl L., Tichy M., Pecka M. Leucine metabolism in rat liver after a bolus injection of endotoxin. Metabolism. 1998;47:681–685. doi: 10.1016/S0026-0495(98)90030-0. PubMed DOI

Holeček M., Muthný T., Kovařík M., Šišpera L. Simultaneous infusion of glutamine and branched-chain amino acids (BCAA) to septic rats does not have more favorable effect on protein synthesis in muscle, liver, and small intestine than separate infusions. JPEN J. Parenter. Enter. Nutr. 2006;30:467–473. doi: 10.1177/0148607106030006467. PubMed DOI

Abumrad N.N., Wise K.L., Williams P.E., Abumrad N.A., Lacy W.W. Disposal of alpha-ketoisocaproate: Roles of liver, gut, and kidneys. Am. J. Physiol. 1982;243:E123–E131. doi: 10.1152/ajpendo.1982.243.2.E123. PubMed DOI

Khatra B.S., Chawla R.K., Sewell C.W., Rudman D. Distribution of branched-chain alpha-keto acid dehydrogenases in primate tissues. J. Clin. Investig. 1977;59:558–564. doi: 10.1172/JCI108671. PubMed DOI PMC

Okita M., Watanabe A., Takei N., Nagashima H., Ubuka T. Effects of branched-chain alpha-keto acids on plasma amino acid concentrations in carbon tetrachloride-intoxicated rats. J. Nutr. 1984;114:1235–1241. doi: 10.1093/jn/114.7.1235. PubMed DOI

Schauder P. Pharmacokinetic and metabolic interrelationships among branched-chain keto and amino acids in humans. J. Lab. Clin. Med. 1985;106:701–707. PubMed

Mitch W.E., Walser M., Sapir D.G. Nitrogen sparing induced by leucine compared with that induced by its keto analogue, alpha-ketoisocaproate, in fasting obese man. J. Clin. Investig. 1981;67:553–562. doi: 10.1172/JCI110066. PubMed DOI PMC

Tischler M.E., Desautels M., Goldberg A.L. Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J. Biol. Chem. 1982;257:1613–1621. PubMed

Stewart P.M., Walser M., Drachman D.B. Branched-chain ketoacids reduce muscle protein degradation in Duchenne muscular dystrophy. Muscle Nerve. 1982;5:197–201. doi: 10.1002/mus.880050304. PubMed DOI

Sapir D.G., Stewart P.M., Walser M., Moreadith C., Moyer E.D., Imbembo A.L., Rosenshein N.B., Munoz S. Effects of alpha-ketoisocaproate and of leucine on nitrogen metabolism in postoperative patients. Lancet. 1983;1:1010–1014. doi: 10.1016/S0140-6736(83)92643-0. PubMed DOI

Sherwin R.S. The effect of ketone bodies and dietary carbohydrate intake on protein metabolism. Acta Chir. Scand. Suppl. 1981;507:30–40. PubMed

Holeček M. Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions. J. Cachexia Sarcopenia Muscle. 2017;8:529–541. doi: 10.1002/jcsm.12208. PubMed DOI PMC

Maddrey W.C., Weber F.L., Jr., Coulter A.W., Chura C.M., Chapanis N.P., Walser M. Effects of keto analogues of essential amino acids in portal-systemic encephalopathy. Gastroenterology. 1976;71:190–195. doi: 10.1016/S0016-5085(76)80185-0. PubMed DOI

Eriksson L.S., Hagenfeldt L., Wahren J. Intravenous infusion of alpha-oxoisocaproate: Influence on amino acid and nitrogen metabolism in patients with liver cirrhosis. Clin. Sci. (Lond.) 1982;62:285–293. doi: 10.1042/cs0620285. PubMed DOI

Walker S., Götz R., Czygan P., Stiehl A., Lanzinger G., Sieg A., Raedsch R., Kommerell B. Oral keto analogs of branched-chain amino acids in hyperammonemia in patients with cirrhosis of the liver. A double-blind crossover study. Digestion. 1982;24:105–111. doi: 10.1159/000198784. PubMed DOI

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

Scaglia F., Carter S., O’Brien W.E., 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

Brunetti-Pierri N., Lanpher B., Erez A., Ananieva E.A., Islam M., Marini J.C., Sun Q., Yu C., Hegde M., Li J., et al. Phenylbutyrate therapy for maple syrup urine disease. Hum. Mol. Genet. 2011;20:631–640. doi: 10.1093/hmg/ddq507. PubMed DOI PMC

Holecek M., Vodenicarovova M. Phenylbutyrate exerts adverse effects on liver regeneration and amino acid concentrations in partially hepatectomized rats. Int. J. Exp. Pathol. 2016;97:278–284. doi: 10.1111/iep.12190. PubMed DOI PMC

Batshaw M., Brusilow S., Walser M. Treatment of carbamyl phosphate synthetase deficiency with keto analogues of essential amino acids. N. Engl. J. Med. 1975;292:1085–1090. doi: 10.1056/NEJM197505222922101. PubMed DOI

Thoene J., Batshaw M., Spector E., Kulovich S., Brusilow S., Walser M., Nyhan W. Neonatal citrllinemia: Treatment with keto-analogues of essential amino acids. J. Pediatr. 1977;90:218–224. doi: 10.1016/S0022-3476(77)80633-1. PubMed DOI

Walser M., Batshaw M., Sherwood G., Robinson B., Brusilow S. Nitrogen metabolism in neonatal citrullinaemia. Clin. Sci. Mol. Med. 1977;53:173–181. doi: 10.1042/cs0530173. PubMed DOI

Glasgow A.M., Kraegel J.H., Schulman J.D. Studies of the cause and treatment of hyperammonemia in females with ornithine transcarbamylase deficiency. Pediatrics. 1978;62:30–37. PubMed

McReynolds J.W., Mantagos S., Brusilow S., Rosenberg L.E. Treatment of complete ornithine transcarbamylase deficiency with nitrogen-free analogues of essential amino acids. J. Pediatr. 1978;93:421–427. doi: 10.1016/S0022-3476(78)81149-4. PubMed DOI

Mero A. Leucine supplementation and intensive training. Sports Med. 1999;27:347–358. doi: 10.2165/00007256-199927060-00001. PubMed DOI

Graham T.E., Bangsbo J., Gollnick P.D., Juel C., Saltin B. Ammonia metabolism during intense dynamic exercise and recovery in humans. Am. J. Physiol. 1990;259:E170–E176. doi: 10.1152/ajpendo.1990.259.2.E170. PubMed DOI

Hellsten Y. The effect of muscle contraction on the regulation of adenosine formation in rat skeletal muscle cells. J. Physiol. 1999;518:761–768. doi: 10.1111/j.1469-7793.1999.0761p.x. PubMed DOI PMC

Shimomura Y., Murakami T., Nakai N., Nagasaki M., Harris R.A. Exercise promotes BCAA catabolism: Effects of BCAA supplementation on skeletal muscle during exercise. J. Nutr. 2004;134:S1583–S1587. doi: 10.1093/jn/134.6.1583S. PubMed DOI

Fouré A., Bendahan D. Is branched-chain amino acids supplementation an efficient nutritional strategy to alleviate skeletal muscle damage? A systematic review. Nutrients. 2017;9:10. PubMed PMC

Greer B.K., White J.P., Arguello E.M., Haymes E.M. Branched-chain amino acid supplementation lowers perceived exertion but does not affect performance in untrained males. J. Strength Cond. Res. 2011;25:539–544. doi: 10.1519/JSC.0b013e3181bf443a. PubMed DOI

Negro M., Giardina S., Marzani B., Marzatico F. Branched-chain amino acid supplementation does not enhance athletic performance but affects muscle recovery and the immune system. J. Sports Med. Phys. Fitness. 2008;48:347–351. PubMed

Kephart W.C., Mumford P.W., McCloskey A.E., Holland A.M., Shake J.J., Mobley C.B., Jagodinsky A.E., Weimar W.H., Oliver G.D., Young K.C., et al. Post-exercise branched chain amino acid supplementation does not affect recovery markers following three consecutive high intensity resistance training bouts compared to carbohydrate supplementation. J. Int. Soc. Sports Nutr. 2016;13:30. doi: 10.1186/s12970-016-0142-y. PubMed DOI PMC

de Almeida R.D., Prado E.S., Llosa C.D., Magalhães-Neto A., Cameron L.C. Acute supplementation with keto analogues and amino acids in rats during resistance exercise. Br. J. Nutr. 2010;104:1438–1442. doi: 10.1017/S0007114510002321. PubMed DOI

Prado E.S., de Rezende Neto J.M., de Almeida R.D., Dória de Melo M.G., Cameron L.C. Keto analogue and amino acid supplementation affects the ammonaemia response during exercise under ketogenic conditions. Br. J. Nutr. 2011;105:1729–1733. doi: 10.1017/S000711451000557X. PubMed DOI

Liu Y., Lange R., Langanky J., Hamma T., Yang B., Steinacker J.M. Improved training tolerance by supplementation with α-Keto acids in untrained young adults: A randomized, double blind, placebo-controlled trial. J. Int. Soc. Sports Nutr. 2012;9:37. doi: 10.1186/1550-2783-9-37. PubMed DOI PMC

Liu Y., Spreng T., Lehr M., Yang B., Karau A., Gebhardt H., Steinacker J.M. The supportive effect of supplementation with α-keto acids on physical training in type 2 diabetes mellitus. Food Funct. 2015;6:2224–2230. doi: 10.1039/C5FO00263J. PubMed DOI

Camerino S.R., Lima R.C., França T.C., Herculano Ede A., Rodrigues D.S., Gouveia M.G., Cameron L.C., Prado E.S. Keto analogue and amino acid supplementation and its effects on ammonemia and performance under thermoneutral conditions. Food Funct. 2016;7:872–880. doi: 10.1039/C5FO01054C. PubMed DOI

Lima R.C.P., Camerino S.R.A.S., França T.C.L., Rodrigues D.S.A., Gouveia M.G.S., Ximenes-da-Silva A., Bassini A., Prado E.S., Cameron L.C. Keto analogues and amino acids supplementation induces a decrease of white blood cell counts and a reduction of muscle damage during intense exercise under thermoneutral conditions. Food Funct. 2017;8:1519–1525. doi: 10.1039/C7FO00189D. PubMed DOI

Why Are Branched-Chain Amino Acids Increased in Starvation and Diabetes?