Branch chain amino acids (BCAAs) have unique properties with diverse physiological and metabolic roles. They have functions other than simple nutrition. Different diseases including metabolic disease lead to protein loss, especially muscle protein. Supplementation of BCAAs promotes protein synthesis and reduces break down, as well as improving disease conditions. They are important regulators of mTOR signaling pathway and regulate protein synthesis as well as protein turnover. BCAAs facilitate glucose uptake by liver and SK muscle and also enhance glycogen synthesis. Oxidation of BCAAs seems to be beneficial for metabolic health as their catabolism increases fatty acid oxidation and reduces risk of obesity. BCAAs are also important in immunity, brain function, and other physiological aspects of well-being. All three BCAAs are absolutely required for lymphocyte growth and proliferation. They are also important for proper immune cell function. BCAAs may influence brain protein synthesis, and production of energy and may influence synthesis of different neurotransmitters. BCAAs can be used therapeutically and future studies may be directed to investigating the diverse effects of BCAAs in different tissues and their signaling pathways. 1. Introduction Amino acids (AAs) are biologically important compounds containing carboxylic and amine moiety as functional groups and are the building blocks of protein. They play important metabolic and physiological roles in all living organisms. Although more than 300 AAs have been found, only 20 AAs are known as standard AA and contain a specific side-chain specific to each AA [1]. Three branch chain amino acids (BCAAs), including isoleucine, leucine, and valine, have unique properties with diverse physiological and metabolic roles. BCAAs are primarily oxidized in the peripheral tissue, in particular in skeletal (SK) muscle, whereas the other AA catabolizes in the liver. BCAAs may regulate rate of protein synthesis and degradation in SK muscle and other organs. BCAAs and aromatic AA bind to the same carrier proteins to be transported to brain. They compete with each other and their ratio in brain may influence the synthesis of specific neurotransmitters, and that may influence the behavior of an organism [2, 3]. BCAAs have glycogen sparing action and they have an opposite relation with tryptophan levels of brain, which is the precursor of serotonin. Serotonin is a mediator of central fatigue. Thus supplementation of BCAAs may prevent fatigue during extensive exercise, and diet enriched with BCAAs may improve muscle
References
[1]
G. Wu, “Amino acids: metabolism, functions, and nutrition,” Amino Acids, vol. 37, no. 1, pp. 1–17, 2009.
[2]
B. Skeie, V. Kvetan, K. M. Gil, M. M. Rothkopf, E. A. Newsholme, and J. Askanazi, “Branch-chain amino acids: their metabolism and clinical utility,” Critical Care Medicine, vol. 18, no. 5, pp. 549–571, 1990.
[3]
J. D. Fernstrom, “Branched-chain amino acids and brain function,” Journal of Nutrition, vol. 135, supplement 6, pp. 1539S–1546S, 2005.
[4]
H. Kainulainen, J. J. Hulmi, and U. M. Kujala, “Potential role of branched-chain amino acid catabolism in regulating fat oxidation,” Exercise and Sport Sciences Reviews, vol. 41, no. 48, pp. 194–200, 2013.
[5]
E. Mori, M. Hasebe, and K. Kobayashi, “Effect of total parenteral nutrition enriched in branched-chain amino acids on metabolite levels in septic rats,” Metabolism, vol. 37, no. 9, pp. 824–830, 1988.
[6]
G. L. Blackburn, L. L. Moldawer, S. Usui, A. Bothe Jr., S. J. D. O'Keefe, and B. R. Bistrian, “Branched chain amino acid administration and metabolism during starvation, injury, and infection,” Surgery, vol. 86, no. 2, pp. 307–315, 1979.
[7]
H. Mochizuki, O. Trocki, L. Dominioni, and J. W. Alexander, “Effect of a diet rich in branched chain amino acids on severely burned guinea pigs,” Journal of Trauma, vol. 26, no. 12, pp. 1077–1085, 1986.
[8]
K. Tajiri and Y. Shimizu, “Branched-chain amino acids in liver diseases,” World Journal of Gastroenterology, vol. 19, no. 43, pp. 7620–7629, 2013.
[9]
K. Sugiyama, L. Yu, and N. Nagasue, “Direct effect of branched-chain amino acids on the growth and metabolism of cultured human hepatocellular carcinoma cells,” Nutrition and Cancer, vol. 31, no. 1, pp. 62–68, 1998.
[10]
T. Kawaguchi, Y. Nagao, H. Matsuoka, T. Ide, and M. Sata, “Branched-chain amino acid-enriched supplementation improves insulin resistance in patients with chronic liver disease,” International Journal of Molecular Medicine, vol. 22, no. 1, pp. 105–112, 2008.
[11]
M. Arakawa, T. Masaki, J. Nishimura, M. Seike, and H. Yoshimatsu, “The effects of branched-chain amino acid granules on the accumulation of tissue triglycerides and uncoupling proteins in diet-induced obese mice,” Endocrine Journal, vol. 58, no. 3, pp. 161–170, 2011.
[12]
M. Kuwahata, H. Kubota, H. Kanouchi et al., “Supplementation with branched-chain amino acids attenuates hepatic apoptosis in rats with chronic liver disease,” Nutrition Research, vol. 32, no. 7, pp. 522–529, 2012.
[13]
K. Ichikawa, T. Okabayashi, Y. Shima et al., “Branched-chain amino acid-enriched nutrients stimulate antioxidant DNA repair in a rat model of liver injury induced by carbon tetrachloride,” Molecular Biology Reports, vol. 39, no. 12, pp. 10803–10810, 2012.
[14]
H. R. Freund and M. Hanani, “The metabolic role of branched-chain amino acids,” Nutrition, vol. 18, no. 3, pp. 287–288, 2002.
[15]
A. L. Goldberg and R. Odessey, “Oxidation of amino acids by diaphragms from fed and fasted rats.,” The American Journal of Physiology, vol. 223, no. 6, pp. 1384–1391, 1972.
[16]
M. G. Buse and S. S. Reid, “Leucine: a possible regulator of protein turnover in muscle,” Journal of Clinical Investigation, vol. 56, no. 5, pp. 1250–1261, 1975.
[17]
J. de Bandt and L. Cynober, “Therapeutic use of branched-chain amino acids in burn, trauma, and sepsis,” Journal of Nutrition, vol. 136, supplement, no. 1, pp. 308S–313S, 2006.
[18]
E. Blomstrand, “Potential role of branched-chain amino acid catabolism in regulating fat oxidation,” Journal of Nutrition, vol. 41, no. 4, pp. 194–200, 2006.
[19]
S. Khanna and S. Gopalan, “Role of branched-chain amino acids in liver disease: the evidence for and against,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 10, no. 3, pp. 297–303, 2007.
[20]
T. M. O'Connell, “The complex role of branched chain amino acids in diabetes and cancer,” Metabolites, vol. 3, no. 4, pp. 931–945, 2013.
[21]
R. Odessey and B. Parr, “Effect of insulin and leucine on protein turnover in rat soleus muscle after burn injury,” Metabolism, vol. 31, no. 1, pp. 82–87, 1982.
[22]
J. C. Manelli, M. Garabedian, N. Ounis, M. Houvenaeghel, A. Ottomani, and J. Bimar, “Effects on muscular and general proteolysis in burn patients of a solution enriched with branched amino acids,” Annales Fran？aises d'Anesthésie et de Réanimation, vol. 3, no. 4, pp. 256–260, 1984.
[23]
M. Hole？ek, “Glutamine and branched-chain amino acids—practical importance of their metabolic relations,” Casopis Lekaru Ceskych, vol. 144, no. 3, pp. S9–S12, 2005.
[24]
S. R. Kimball and L. S. Jefferson, “Regulation of protein synthesis by branched-chain amino acids,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 4, no. 1, pp. 39–43, 2001.
[25]
J. B. Li and L. S. Jefferson, “Influence of amino acid availability on protein turnover in perfused skeletal muscle,” Biochimica et Biophysica Acta, vol. 544, no. 2, pp. 351–359, 1978.
[26]
M. G. Buse, R. Atwell, and V. Mancusi, “In vitro effect of branched chain amino acids on the ribosomal cycle in muscles of fasted rats,” Hormone and Metabolic Research, vol. 11, no. 4, pp. 289–292, 1979.
[27]
E. J. Brown, M. W. Albers, K. Ichikawa, C. T. Keith, W. S. Lane, and S. L. Schreiber, “A mammalian protein targeted by G1-arresting rapamycin-receptor complex,” Nature, vol. 369, no. 6483, pp. 756–758, 1994.
[28]
N. Hay and N. Sonenberg, “Upstream and downstream of mTOR,” Genes and Development, vol. 18, no. 16, pp. 1926–1945, 2004.
[29]
C. Ijichi, T. Matsumura, T. Tsuji, and Y. Eto, “Branched-chain amino acids promote albumin synthesis in rat primary hepatocytes through the mTOR signal transduction system,” Biochemical and Biophysical Research Communications, vol. 303, no. 1, pp. 59–64, 2003.
[30]
J. C. Anthony, F. Yoshizawa, T. G. Anthony, T. C. Vary, L. S. Jefferson, and S. R. Kimball, “Leucine stimulates translation initiation skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway,” Journal of Nutrition, vol. 130, no. 10, pp. 2413–2419, 2000.
[31]
S. Nishitani, C. Ijichi, K. Takehana, S. Fujitani, and I. Sonaka, “Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction,” Biochemical and Biophysical Research Communications, vol. 313, no. 2, pp. 387–389, 2004.
[32]
S. Nishitani, T. Matsumura, S. Fujitani, I. Sonaka, Y. Miura, and K. Yagasaki, “Leucine promotes glucose uptake in skeletal muscles of rats,” Biochemical and Biophysical Research Communications, vol. 299, no. 5, pp. 693–696, 2002.
[33]
K. Peyrollier, E. Hajduch, A. S. Blair, R. Hyde, and H. S. Hundal, “L- leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin ( mTOR ) pathway in the L- leucine -induced up-regulation of system A amino acid transport,” The Biochemical Journal, vol. 350, part 2, pp. 361–368, 2000.
[34]
J. Nishimura, T. Masaki, M. Arakawa, M. Seike, and H. Yoshimatsu, “Isoleucine prevents the accumulation of tissue triglycerides and upregulates the expression of PPARγ and uncoupling protein in diet-induced obese mice,” Journal of Nutrition, vol. 140, no. 3, pp. 496–500, 2010.
[35]
A. B. Gualano, T. Bozza, P. de Lopes Campos et al., “Branched-chain amino acids supplementation enhances exercise capacity and lipid oxidation during endurance exercise after muscle glycogen depletion,” Journal of Sports Medicine and Physical Fitness, vol. 51, no. 1, pp. 82–88, 2011.
[36]
L. Q. Qin, P. Xun, D. Bujnowski et al., “Higher branched-chain amino acid intake is associated with a lower prevalence of being overweight or obese in middle-aged East Asian and Western adults,” Journal of Nutrition, vol. 141, no. 2, pp. 249–254, 2011.
[37]
S. D. Skaper, D. P. Molden, and J. E. Seegmiller, “Maple syrup urine disease: branched-chain amino acid concentrations and metabolism in cultured human lymphoblasts,” Biochemical Genetics, vol. 14, no. 7-8, pp. 527–539, 1976.
[38]
G. Schafer and P. Schauder, “Assessment of effects of amino acids and branched chain keto acids on leucine oxidation in human lymphocytes,” Scandinavian Journal of Clinical & Laboratory Investigation, vol. 48, no. 6, pp. 531–536, 1988.
[39]
P. Schauder and G. Schafer, “Oxidation of leucine in human lymphocytes,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 47, no. 5, pp. 447–453, 1987.
[40]
P. C. Calder, “Branched-chain amino acids and immunity,” The Journal of Nutrition, vol. 136, supplement 1, no. 1, pp. 288S–293S, 2006.
[41]
T. M. Petro and J. K. Bhattacharjee, “Effect of dietary essential amino acid limitations upon the susceptibility to Salmonella typhimurium and the effect upon humoral and cellular immune responses in mice,” Infection and Immunity, vol. 32, no. 1, pp. 251–259, 1981.
[42]
F. B. Cerra, J. E. Mazuski, E. Chute et al., “Branched chain metabolic support. A prospective randomized, double-blind trial in surgical stress,” Annals of Surgery, vol. 199, no. 3, pp. 286–291, 1984.
[43]
R. A. Bassit, L. A. Sawada, R. F. P. Bacurau et al., “Branched-chain amino acid supplementation and the immune response of long-distance athletes,” Nutrition, vol. 18, no. 5, pp. 376–379, 2002.
[44]
M. M. Levy, M. P. Fink, J. C. Marshall et al., “2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference,” Critical Care Medicine, vol. 31, no. 4, pp. 1250–1256, 2003.
[45]
A. García-de-Lorenzo, C. Ortiz-Leyba, M. Planas et al., “Parenteral administration of different amounts of branch-chain amino acids in septic patients: clinical and metabolic aspects,” Critical Care Medicine, vol. 25, no. 3, pp. 418–424, 1997.
[46]
B. C. Batch, K. Hyland, and L. P. Svetkey, “Branch chain amino acids: biomarkers of health and disease,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 17, no. 1, pp. 86–89, 2014.
[47]
F. Xu, S. Tavintharan, C. F. Sum, K. Woon, S. C. Lim, and C. N. Ong, “Metabolic signature shift in type 2 diabetes mellitus revealed by mass spectrometry-based metabolomics,” Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 6, pp. E1060–E1065, 2013.
[48]
B. C. Melnik, “Leucine signaling in the pathogenesis of type 2 diabetes and obesity,” World Journal of Diabetes, vol. 3, no. 3, pp. 38–53, 2012.
[49]
A. F. Sved, J. D. Fernstrom, and R. J. Wurtman, “Tyrosine administration reduces blood pressure and enhances brain norepinephrine release in spontaneously hypertensive rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 7, pp. 3511–3514, 1979.
