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Tolerability of Leucine in Humans

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Branched Chain Amino Acids in Clinical Nutrition

Abstract

Use of dietary supplements, especially among athletes is increasing. Among the amino acids, the branched-chain amino acids (BCAA-leucine, valine and isoleucine) are popular as dietary supplements especially among strength training athletes. In particular, leucine as a supplement is widely consumed because it has been implicated to be the key amino acid involved in stimulating muscle protein synthesis. This chapter will present current dietary leucine intakes, define the concept of safe upper limits (UL) and summarize a recent study in humans conducted to address leucine tolerability. In the 2005 Dietary References Intake (DRI) report, men 51 through 70 years of age had the highest intakes, at the 99th percentile for leucine, at 14,100 mg·d-1 (~ 201 mg·kg·d-1). In order to directly explore leucine tolerability in humans we proposed a novel model. We hypothesized that with increasing intakes of leucine above the estimated average requirement (EAR of 50 mg·kg-1·d-1) in adult men, the oxidation of leucine will increase and will reach a maximum, after which the leucine oxidation will achieve a plateau. This ‘metabolic limit’ to oxidize leucine may be used as a marker of an intake after which increasing intakes may result in increasing risk of adverse effects. Five healthy young men participated in the study. Each subject participated in a dose-escalation study design, where graded stepwise increases in leucine intake (150, 250, 500, 750, 1000 and 1250 mg·kg-1·d-1 corresponding to the EAR, EARx3, x5, x10, x15, x20 and x25) were provided on each study day. Oxidation of L-[1-13C]leucine to 13CO2 in breath (F13CO2) was measured on each study day. With increasing intakes of leucine, a dose-response in leucine oxidative capacity was observed, with a breakpoint estimated at 550 mg·kg-1·d-1 or 39 g·d-1. Simultaneous and significant increases in blood ammonia concentrations, plasma leucine concentrations and urinary leucine excretion were observed with leucine intakes higher than 500 mg·kg-1·d-1. These results taken together with the recent animal data suggest that under acute dietary conditions, as a cautious estimate, intakes greater than 500 mg leucine·kg-1·d-1 may potentially increase the risk of adverse events, and could be proposed as the UL for leucine in healthy adults.

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References

  1. Maughan RJ, Depiesse F, Geyer H, International Association of Athletics Federations. The use of dietary supplements by athletes. J Sports Sci. 2007;25:S103–13.

    Article  PubMed  Google Scholar 

  2. Lun V, Erdman KA, Fung TS, et al. Dietary supplementation practices in Canadian high-performance athletes. Int J Sport Nutr Exerc Metab. 2012;22:31–7.

    CAS  PubMed  Google Scholar 

  3. Braun H, Koehler K, Geyer H, et al. Dietary supplement use among elite young German athletes. Int J Sport Nutr Exerc Metab. 2009;19:97–109.

    PubMed  Google Scholar 

  4. Young VR. Introduction to the 2nd amino acid assessment workshop. J Nutr. 2003;133:2015S–20.

    CAS  PubMed  Google Scholar 

  5. Buse MG, Reid SS. Leucine. A possible regulator of protein turnover in muscle. J Clin Invest. 1975;56:1250–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Anthony JC, Yoshizawa F, Anthony TG, et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr. 2000;130:2413–9.

    CAS  PubMed  Google Scholar 

  7. Crozier SJ, Kimball SR, Emmert SW, et al. Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J Nutr. 2005;135:376–82.

    CAS  PubMed  Google Scholar 

  8. Nair KS, Short KR. Hormonal and signaling role of branched-chain amino acids. J Nutr. 2005;135:1547S–52.

    CAS  PubMed  Google Scholar 

  9. Pitkänen HT, Oja SS, Rusko H, et al. Leucine supplementation does not enhance acute strength or running performance but affects serum amino acid concentration. Amino Acids. 2003;25:85–94.

    Article  PubMed  Google Scholar 

  10. Mero A. Leucine supplementation and intensive training. Sports Med. 1999;27:347–58.

    Article  CAS  PubMed  Google Scholar 

  11. Crowe MJ, Weatherson JN, Bowden BF. Effects of dietary leucine supplementation on exercise performance. Eur J Appl Physiol. 2006;97:664–72.

    Article  CAS  PubMed  Google Scholar 

  12. Coburn JW, Housh DJ, Housh TJ, et al. Effects of leucine and whey protein supplementation during eight weeks of unilateral resistance training. J Strength Cond Res. 2006;20:284–91.

    PubMed  Google Scholar 

  13. Shimomura Y, Inaguma A, Watanabe S, et al. Branched-chain amino acid supplementation before squat exercise and delayed-onset muscle soreness. Int J Sport Nutr Exerc Metab. 2010;20:236–44.

    CAS  PubMed  Google Scholar 

  14. Walker TB, Smith J, Herrera M, et al. The influence of 8 weeks of whey-protein and leucine supplementation on physical and cognitive performance. Int J Sport Nutr Exerc Metab. 2010;20:409–17.

    CAS  PubMed  Google Scholar 

  15. Thomson JS, Ali A, Rowlands DS. Leucine-protein supplemented recovery feeding enhances subsequent cycling performance in well-trained men. Appl Physiol Nutr Metab. 2011;36:242–53.

    Article  CAS  PubMed  Google Scholar 

  16. Ispoglou T, King RF, Polman RC, et al. Daily L-leucine supplementation in novice trainees during a 12-week weight training program. Int J Sports Physiol Perform. 2011;6:38–50.

    PubMed  Google Scholar 

  17. Verhoeven S, Vanschoonbeek K, Verdijk LB, et al. Long-term leucine supplementation does not increase muscle mass or strength in healthy elderly men. Am J Clin Nutr. 2009;89:1468–75.

    Article  CAS  PubMed  Google Scholar 

  18. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Energy, Carbohydrate, Fiber, fat, Fatty Acids, Cholesterol, Protein and Amino Acids. Washington, DC: The National Academy Press; 2005.

    Google Scholar 

  19. Millward DJ. Knowledge gained from studies of leucine consumption in animals and humans. J Nutr. 2012;142:2212S–9.

    Article  CAS  PubMed  Google Scholar 

  20. Fernstrom JD. Branched-chain amino acids and brain function. J Nutr. 2005;135:1539S–46.

    CAS  PubMed  Google Scholar 

  21. Matthews DE. Observations of branched-chain amino acid administration in humans. J Nutr. 2005;135:1580S–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Pencharz PB, Elango R, Ball RO. An approach to defining the upper safe limits of amino acid intake. J Nutr. 2008;138:1996S–2002.

    CAS  PubMed  Google Scholar 

  23. House JD, Pencharz PB, Ball RO. Phenylalanine requirements determined by using L-[1-14C]phenylalanine in neonatal piglets receiving total parenteral nutrition supplemented with tyrosine. Am J Clin Nutr. 1997;65:984–93.

    CAS  PubMed  Google Scholar 

  24. Sakai R, Miura M, Amao M, et al. Potential approaches to the assessment of amino acid adequacy in rats: a progress report. J Nutr. 2004;134:1651S–5.

    CAS  PubMed  Google Scholar 

  25. Tsubuku S, Hatayama K, Katsumata T, et al. Thirteen-week oral toxicity study of branched-chain amino acids in rats. Int J Toxicol. 2004;23:119–26.

    Article  CAS  PubMed  Google Scholar 

  26. Mawatari K, Katsumata T, Uematsu M, et al. Prolonged oral treatment with an essential amino acid L-leucine does not affect female reproductive function and embryo-fetal development in rats. Food Chem Toxicol. 2004;42:1505–11.

    Article  CAS  PubMed  Google Scholar 

  27. Imamura W, Yoshimura R, Takai M, et al. Adverse effects of excessive leucine intake depend on dietary protein intake: a transcriptomic analysis to identify useful biomarkers. J Nutr Sci Vitaminol (Tokyo). 2013;59:45–55.

    Article  CAS  Google Scholar 

  28. Baker DH. Tolerance for branched-chain amino acids in experimental animals and humans. J Nutr. 2005;135:1585S–90.

    CAS  PubMed  Google Scholar 

  29. Elango R, Chapman K, Rafii M, et al. Determination of the tolerable upper intake level of leucine in acute dietary studies in young men. Am J Clin Nutr. 2012;96:759–67.

    Article  CAS  PubMed  Google Scholar 

  30. Riazi R, Wykes LJ, Ball RO, et al. The total branched-chain amino acid requirement in young healthy adult men determined by indicator amino acid oxidation by use of L-[1-13C]phenylalanine. J Nutr. 2003;133:1383–9.

    CAS  PubMed  Google Scholar 

  31. Littell R, Milliken G, Stroup W, Wolfinger R. SAS System for Mixed Models. Cary, NC: SAS Institute; 1996.

    Google Scholar 

  32. Seber GAF. Linear regression analysis. Wiley: New York, NY; 1977.

    Google Scholar 

  33. Pencharz PB, Elango R, Ball RO. Determination of the tolerable upper intake level of leucine in adult men. J Nutr. 2012;142:2220S–4.

    Article  CAS  PubMed  Google Scholar 

  34. Nair KS, Matthews DE, Welle SL, et al. Effect of leucine on amino acid and glucose metabolism in humans. Metabolism. 1992;41:643–8.

    Article  CAS  PubMed  Google Scholar 

  35. Kalogeropoulou D, Lafave L, Schweim K, et al. Leucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucose. Metabolism. 2008;57:1747–52.

    Article  CAS  PubMed  Google Scholar 

  36. Harper AE, Miller RH, Block KP. Branched-chain amino acid metabolism. Annu Rev Nutr. 1984;4:409–54.

    Article  CAS  PubMed  Google Scholar 

  37. Block KP, Harper AE. Valine metabolism in vivo: effects of high dietary levels of leucine and isoleucine. Metabolism. 1984;33:559–66.

    Article  CAS  PubMed  Google Scholar 

  38. Eriksson S, Hagenfeldt L, Wahren J. A comparison of the effects of intravenous infusion of individual branched-chain amino acids on blood amino acid levels in man. Clin Sci (Lond). 1981;60:95–100.

    CAS  Google Scholar 

  39. Hambraeus L, Bilmazes C, Dippel C, et al. Regulatory role of dietary leucine on plasma branched-chain amino acid levels in young men. J Nutr. 1976;106:230–40.

    CAS  PubMed  Google Scholar 

  40. Aftring RP, Block KP, Buse MG. Leucine and isoleucine activate skeletal muscle branched-chain alpha-keto acid dehydrogenase in vivo. Am J Physiol. 1986;250:E599–604.

    CAS  PubMed  Google Scholar 

  41. Stanley CA. Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children. Am J Clin Nutr. 2009;90:862S–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Erecińska M, Nelson D. Activation of glutamate dehydrogenase by leucine and its nonmetabolizable analogue in rat brain synaptosomes. J Neurochem. 1990;54:1335–43.

    Article  PubMed  Google Scholar 

  43. Coude FX, Sweetman L, Nyhan WL. Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest. 1979;64:1544–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Phillips SM. Protein requirements and supplementation in strength sports. Nutrition. 2004;20:689–95.

    Article  CAS  PubMed  Google Scholar 

  45. Gleeson M. Interrelationship between physical activity and branched-chain amino acids. J Nutr. 2005;135:1591S–5.

    CAS  PubMed  Google Scholar 

  46. Balage M, Dardevet D. Long-term effects of leucine supplementation on body composition. Curr Opin Clin Nutr Metab Care. 2010;13:265–70.

    Article  CAS  PubMed  Google Scholar 

  47. Cynober L, Bier DM, Kadowaki M, et al. A proposal for an upper limit of leucine safe intake in healthy adults. J Nutr. 2012;142:2249S–50.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Rajavel Elango Ph.D. .

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Elango, R., Ball, R.O., Pencharz, P.B. (2015). Tolerability of Leucine in Humans. In: Rajendram, R., Preedy, V., Patel, V. (eds) Branched Chain Amino Acids in Clinical Nutrition. Nutrition and Health. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1914-7_1

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  • DOI: https://doi.org/10.1007/978-1-4939-1914-7_1

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