Leucine is a major regulator of muscle protein synthesis in neonates

Abstract

Approximately 10 % of infants born in the United States are of low birth weight. Growth failure during the neonatal period is a common occurrence in low birth weight infants due to their inability to tolerate full feeds, concerns about advancing protein supply, and high nutrient requirements for growth. An improved understanding of the nutritional regulation of growth during this critical period of postnatal growth is vital for the development of strategies to improve lean gain. Past studies with animal models have demonstrated that muscle protein synthesis is increased substantially following a meal and that this increase is due to the postprandial rise in amino acids as well as insulin. Both amino acids and insulin act independently to stimulate protein synthesis in a mammalian target of rapamycin-dependent manner. Further studies have elucidated that leucine, in particular, and its metabolites, α-ketoisocaproic acid and β-hydroxy-β-methylbutyrate, have unique anabolic properties. Supplementation with leucine, provided either parenterally or enterally, has been shown to enhance muscle protein synthesis in neonatal pigs, making it an ideal candidate for stimulating growth of low birth weight infants.

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Abbreviations

4EBP1:

4E-binding protein 1

AA:

Amino acids

Akt/PKB:

Protein kinase B

BCAA:

Branched-chain amino acids

BOL:

Bolus fed

CON:

Continuously fed

CON+LEU:

Continuously fed and pulsed with leucine

eIF4E:

Eukaryotic initiation factor 4E

eIF4G:

Eukaryotic initiation factor 4G

HMB:

β-Hydroxy-β-methylbutyrate

KIC:

α-Ketoisocaproic acid

mTOR:

Mammalian target of rapamycin

S6:

Ribosomal protein S6

S6K1:

Ribosomal protein S6 kinase 1

References

  1. Abdelhamid AE, Chuang SL, Hayes P, Fell JM (2011) In vitro cow’s milk protein-specific inflammatory and regulatory cytokine responses in preterm infants with necrotizing enterocolitis and sepsis. Pediatr Res 69:165–169

    CAS  PubMed  Article  Google Scholar 

  2. Anthony JC, Anthony TG, Kimball SR, Vary TC, Jefferson LS (2000) Orally administered leucine stimulates protein synthesis in skeletal muscle of postabsorptive rats in association with increased eIF4F formation. J Nutr 130:139–145

    CAS  PubMed  Google Scholar 

  3. Atherton PJ, Etheridge T, Watt PW, Wilkinson D, Selby A, Rankin D, Smith K, Rennie MJ (2010a) Muscle full effect after oral protein: time-dependent concordance and discordance between human muscle protein synthesis and mTORC1 signaling. Am J Clin Nutr 92:1080–1088

    CAS  PubMed  Article  Google Scholar 

  4. Atherton PJ, Smith K, Etheridge T, Rankin D, Rennie MJ (2010b) Distinct anabolic signaling responses to amino acids in C2C12 skeletal muscle cells. Amino Acids 38:1533–1539

    CAS  PubMed  Article  Google Scholar 

  5. Baille AGS, Garlick PJ (1991) Attenuated responses of muscle protein synthesis to fasting and insulin in adult female rats. Am J Physiol Endocrinol Metab 25:E1–E5

    Google Scholar 

  6. Barker DJ (2004) The developmental origins of adult disease. J Am Coll Nutr 23:588S–595S

    CAS  PubMed  Article  Google Scholar 

  7. Bennet WM, Connacher AA, Scrimgeour RT, Smith K, Rennie MJ (1989) Increase in anterior tibialis muscle protein synthesis in healthy man during mixed amino acid infusion: studies of incorporation of [1-13C] leucine. Clin Sci (Lond) 76:447–454

    CAS  Google Scholar 

  8. Bennet WM, Connacher AA, Scrimgeour CM, Jung RT, Rennie MJ (1990) Euglycemichyperinsulinemia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am J Physiol Endocrinol Metab 259:E185–E194

    CAS  Google Scholar 

  9. Berseth CL (2001) Feeding methods for the preterm infant. Semin Neonatol 6:417–424

    CAS  PubMed  Article  Google Scholar 

  10. Borsheim E, Tipton KD, Wolf SE, Wolfe RR (2002) Essential amino acids and muscle protein recovery from resistance exercise. Am J Physiol Endocrinol Metab 283:E648–E657

    CAS  PubMed  Google Scholar 

  11. Boutry C, El-Kadi SW, Suryawan A, Wheatley SM, Orellana RA, Kimball SR, Nguyen HV, Davis TA (2013) Leucine pulses enhance skeletal muscle protein synthesis during continuous feeding in neonatal pigs. Am J Physiol Endocrinol Metab 305:E620–E631

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. Brown LD (2014) Endocrine regulation of fetal skeletal muscle growth: impact on future metabolic health. J Endocrinol 221:R13–R29

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  13. Burrin DG, Davis TA (2013) Mechanisms of nutrient sensing. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR (eds) Modern nutrition in health and disease, 11th edn, Part II. Nutritional roles in integrated biologic systems, section B. Digestive, endocrine, immune, and neural mechanisms. Williams and Wilkins Publishers, Philadelphia, pp 626–632

    Google Scholar 

  14. Burrin DG, Shulman RJ, Reeds PJ, Davis TA, Gravitt KR (1992) Porcine colostrum and milk stimulate visceral organ and skeletal muscle protein synthesis in neonatal piglets. J Nutr 122:1205–1213

    CAS  PubMed  Google Scholar 

  15. Buse MG, Reid SS (1975) Leucine: a possible regulator of protein turnover in muscle. J Clin Invest 56:1250–1261

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. Churchward-Venne TA, Burd NA, Mitchell CJ, West DWD, Philip A, Marcotte GR, Baker SK, Baar K, Phillips M (2012) Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J Pysiol 590:2751–2765

    CAS  Article  Google Scholar 

  17. Churchward-Venne TA, Breen L, Di Donato DM, Hector AJ, Mitchell CJ, Moore DR, Stellingwerff T, Breuille D, Offord EA, Baker SK, Phillips SM (2014) Leucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a double-blind, randomized trial. Am J Clin Nutr 99:276–286

    CAS  PubMed  Article  Google Scholar 

  18. Cooke R, Embleton N, Rigo J, Carrie A, Haschke F, Ziegler E (2006) High protein pre-term infant formula: effect on nutrient balance, metabolic status and growth. Pediatr Res 59:265–270

    PubMed  Article  Google Scholar 

  19. Cuthbertson D, Smith K, Babraj J, Leese G, Waddell T, Atherton P, Wackerhage H, Taylor PM, Rennie MJ (2005) Anabolic signaling deficits underlie amino acid resistance of wasting, aging muscle. FASEB J 19:422–424

    CAS  PubMed  Google Scholar 

  20. Dangin M, Boirie Y, Garcia-Rodenas C, Gachon P, Fauquant J, Callier P, Ballèvre O, Beaufrère B (2001) The digestion rate of protein is an independent regulating factor of postprandial protein retention. Am J Physiol Endocrinol Metab 280:E340–E348

    CAS  PubMed  Google Scholar 

  21. Davis TA, Fiorotto ML (2009) Regulation of muscle growth in neonates. Curr Opin Clin Nutr Metab Care 2:78–85

    Article  Google Scholar 

  22. Davis TA, Fiorotto ML, Nguyen HV, Reeds PJ (1989) Protein turnover in skeletal muscle of suckling rats. Am J Physiol Reg 26:R1141–R1146

    Google Scholar 

  23. Davis TA, Fiorotto ML, Nguyen HV, Reeds PJ (1993) Enhanced response of muscle protein synthesis and plasma insulin to food intake in suckled rats. Am J Physiol Reg 265:R334–R340

    CAS  Google Scholar 

  24. Davis TA, Burrin DG, Fiorotto ML, Nguyen HV (1996) Protein synthesis in skeletal muscle and jejunum is more responsive to feeding in 7- than in 26-day-old pigs. Am J Physiol Endocrinol Metab 33:E802–E809

    Google Scholar 

  25. Davis TA, Fiorotto ML, Burrin DG, Reeds PJ, Nguyen HV, Beckett PR, Vann RC, O’Connor PM (2002) Stimulation of protein synthesis by both insulin and amino acids is unique to skeletal muscle in neonatal pigs. Am J Physiol Endocrinol Metab 282:E880–E890

    CAS  PubMed  Google Scholar 

  26. Denne SC, Rossi EM, Kalhan SC (1991) Leucine kinetics during feeding in normal newborns. Pediatr Res 30:23–27

    CAS  PubMed  Article  Google Scholar 

  27. Dickinson JM, Fry CS, Drummond MJ, Gundermann DM, Walker DK, Glynn EL, Timmerman KL, Dhanani S, Volpi E, Rasmussen BB (2011) Mammalian target of rapamycin complex 1 activation is required for the stimulation of human skeletal muscle protein synthesis by essential amino acids. J Nutr 141:856–862

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  28. Dollberg S, Kuint J, Mazkereth R, Mimouni FB (2000) Feeding tolerance in preterm infants: randomized trial of bolus and continuous feeding. J Am Coll Nutr 19:797–800

    CAS  PubMed  Article  Google Scholar 

  29. Efeyan A, Zoncu R, Sabatini DM (2012) Amino acids and mTORC1: from lysosomes to disease. Trends Mol Med 18:524–533

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  30. Ehrenkranz RA (2007) Early, aggressive nutritional management for very low birth weight infants: what is the evidence? Semin Perinatol 31:48–55

    PubMed  Article  Google Scholar 

  31. Ehrenkranz RA, Younes N, Lemons JA, Fanaroff AA, Donovan EF, Wright LL, Katsikiotis V, Tyson JE, Oh W, Shankaran S, Bauer CR, Korones SB, Stoll BJ, Stevenson DK, Papile LA (1999) Longitudinal growth of hospitalized very low birth weight infants. Pediatrics 104:280–289

    CAS  PubMed  Article  Google Scholar 

  32. El-Kadi SW, Suryawan A, Gazzaneo MC, Srivastava N, Orellana RA, Nguyen HV, Lobley GE, Davis TA (2012) Anabolic signaling and protein deposition are enhanced by intermittent compared with continuous feeding in skeletal muscle of neonates. Am J Physiol Endocrinol Metab 302:E674–E686

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  33. Escobar J, Frank JW, Suryawan A, Nguyen HV, Kimball SR, Jefferson LS, Davis TA (2005) Physiological rise in plasma leucine stimulates muscle protein synthesis in neonatal pigs by enhancing translation initiation factor activation. Am J Physiol Endocrinol Metab 288:E914–E921

    CAS  PubMed  Article  Google Scholar 

  34. Escobar J, Frank JW, Suryawan A, Nguyen HV, Kimball SR, Jefferson LS, Davis TA (2006) Regulation of cardiac and skeletal muscle protein synthesis by individual branched-chain amino acids in neonatal pigs. Am J Physiol Endocrinol Metab 290:E612–E621

    CAS  PubMed  Article  Google Scholar 

  35. Escobar J, Frank JW, Suryawan A, Nguyen HV, Davis TA (2007) Amino acid availability and age affect the leucine stimulation of protein synthesis and eIF4F formation in muscle. Am J Physiol Endocrinol Metab 293:E1615–E1621

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  36. Escobar J, Frank JW, Suryawan A, Nguyen HV, Van Horn CG, Hutson SM, Davis TA (2010) Leucine and α-ketoisocaproic acid, but not norleucine, stimulate skeletal muscle protein synthesis in neonatal pigs. J Nutr 140:1418–1424

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. FAO (Food and Agriculture Organization of the United Nations) (1970) Amino-acid content of foods. In: Amino-acid content of foods and biological data on proteins. FAO, Rome

  38. Flakoll P, Sharp R, Baier S, Levenhagen D, Carr C, Nissen S (2004) Effect of beta-hydroxy-beta-methylbutyrate, arginine, and lysine supplementation on strength, functionality, body composition, and protein metabolism in elderly women. Nutrition 20:445–451

    CAS  PubMed  Article  Google Scholar 

  39. Ford GW, Doyle LW, Davis NM, Callanan C (2000) Very low birth weight and growth into adolescence. Arch Pediatr Adolesc Med 154:778–784

    CAS  PubMed  Article  Google Scholar 

  40. Frank JW, Escobar J, Suryawan A, Kimball SR, Nguyen HV, Jefferson LS, Davis TA (2005) Protein synthesis and translation initiation factor activation in neonatal pigs fed increasing levels of dietary protein. J Nutr 135:1374–1381

    CAS  PubMed  Google Scholar 

  41. Frank JW, Escobar J, Suryawan A, Nguyen HV, Kimball SR, Jefferson LS, Davis TA (2006) Dietary protein and lactose increase translation initiation factor activation and tissue protein synthesis in neonatal pigs. Am J Physiol Endocrinol Metab 290:E3225–E3233

    Google Scholar 

  42. Garlick PJ, Grant I (1988) Amino acid infusion increases the sensitivity of muscle protein synthesis in vivo to insulin: effect of branched-chain amino acids. Biochem J 254:579–584

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Gazzaneo MC, Suryawan A, Orellana RA, Torrazza RM, El-Kadi SW, Wilson FA, Kimball SR, Srivastava N, Nguyen HV, Fiorotto ML, Davis TA (2011) Intermittent bolus feeding has a greater stimulatory effect on protein synthesis in skeletal muscle than continuous feeding in neonatal pigs. J Nutr 141:2152–2158

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  44. Giordano M, Castellino P, DeFronzo RA (1996) Differential responsiveness of protein synthesis and degradation to amino acid availability in humans. Diabetes 45:393–399

    CAS  PubMed  Article  Google Scholar 

  45. Greenhaff PL, Karagounis LG, Peirce N, Simpson EJ, Hazell M, Layfield R, Wackerhage H, Smith K, Atherton P, Selby A, Rennie MJ (2008) Disassociation between the effects of amino acids and insulin on signaling, ubiquitin ligases, and protein turnover in human muscle. Am J Physiol Endocrinol Metab 295:E595–E604

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  46. Hay WW (2008) Strategies for feeding the preterm infant. Neonatology 94:245–254

    PubMed Central  PubMed  Article  Google Scholar 

  47. Hietakangas V, Stephen Cohen SM (2009) Regulation of tissue growth through nutrient sensing. Annu Rev Genet 43:389–410

    CAS  PubMed  Article  Google Scholar 

  48. Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R, Krouskop RW (2004) Aggressive early total parenteral nutrition in low-birth-weight infants. J Perinatol 24:482–486

    PubMed  Article  Google Scholar 

  49. Johnson JD, Albritton WL, Sunshine P (1972) Hyperammonemia accompanying parenteral nutrition in newborn infants. J Pediatr 81:154–161

    CAS  PubMed  Article  Google Scholar 

  50. Kashyap S, Forsyth M, Zucker C, Ramakrishnan R, Dell RB, Heird WC (1986) Effects of varying protein and energy intakes on growth and metabolic responses in low birth weight infants. J Pediatr 108:955–963

    CAS  PubMed  Article  Google Scholar 

  51. Kashyap S, Okamoto E, Kanaya S, Zucker C, Abildskov K, Dell RB, Heird WC (1988) Growth, nutrient retention, and metabolic response in low birth weight infants fed varying intakes of protein and energy. J Pediatr 133:713–721

    Article  Google Scholar 

  52. Kimball SR (2013) Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle. Am J Clin Nutr 99:237S–242S

    PubMed Central  PubMed  Article  Google Scholar 

  53. Liu Z, Barrett EJ (2002) Human protein metabolism: its measurement and regulation. Am J Physiol Endocrinol Metab 283:E1105–E1112

    CAS  PubMed  Google Scholar 

  54. Liu Z, Jahn LA, Wei L, Long W, Barrett EJ (2002) Amino acids stimulate translation initiation and protein synthesis through an Akt-independent pathway in human skeletal muscle. J Clin Endocrinol Metab 87:5553–5558

    CAS  PubMed  Article  Google Scholar 

  55. Lobley GE (1998) Nutritional and hormonal control of muscle and peripheral tissue metabolism in farm species. Livest Prod Sci 56:91–114

    Article  Google Scholar 

  56. Lobley GE (2003) Protein turnover—what does it mean for animal production? Can J Anim Sci 83:327–340

    CAS  Article  Google Scholar 

  57. Lynch CJ, Patson BJ, Anthony J, Jefferson LS, Vaval A, Vary TC (2002) Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab 283:E503–E513

    CAS  PubMed  Google Scholar 

  58. McNurlan MA, Essen P, Milne E, Vinnars E, Garlick PJ, Wernerman J (1993) Temporal response of protein synthesis in human skeletal muscle to feeding. Br J Nutr 69:117–126

    CAS  PubMed  Article  Google Scholar 

  59. Moore DR, Robinson MJ, Fry JL, Tang JE, Glover EI, Wilkinson SB, Prior T, Tarnopolsky MA, Phillips SM (2009) Ingested protein dose response of muscle and albumin protein synthesis after resistance exercise in young men. Am J Clin Nutr 89:161–168

    CAS  PubMed  Article  Google Scholar 

  60. Nissen S, Sharp R, Ray M, Rathmacher JA, Rice D, Fuller JC, Connelly AS, Abumrad N (1996) Effect of leucine metabolite beta-hydroxy-beta-methylbutyrate on muscle metabolism during resistance-exercise training. J ApplPhysiol 81:2095–2104

    CAS  Google Scholar 

  61. Nissen S, Sharp RL, Panton L, Vukovich M, Trappe S, Fuller JC (2000) β-hydroxy-β-methylbutyrate (HMB) supplementation in humans is safe and may decrease cardiovascular risk factors. J Nutr 130:1937–1945

    CAS  PubMed  Google Scholar 

  62. Norton LE, Wilson GJ, Layman DK, Moulton CJ, Garlick PJ (2012) Leucine content of dietary proteins is a determinant of postprandial skeletal muscle protein synthesis in adult rats. Nutr Metab 9:67–75

    CAS  Article  Google Scholar 

  63. NRC (1998) Nutrient requirements of swine, vol 10. National Academies Press, Washington, D.C

    Google Scholar 

  64. NRC (2012) Nutrient requirements of swine, vol 11. National Academies Press, Washington, D.C

    Google Scholar 

  65. O’Connor PMJ, Bush JA, Suryawan A, Nguyen HV, Davis TA (2003) Insulin and amino acids independently stimulate skeletal muscle protein synthesis in neonatal pigs. Am J Physiol Endocrinol Metab 284:E110–E119

    PubMed  Google Scholar 

  66. Preedy VR, Garlick PJ (1986) The response of muscle protein synthesis to nutrient intake in postabsorptive rats: the role of insulin and amino acids. Biosci Rep 6:177–183

    CAS  PubMed  Article  Google Scholar 

  67. Premji SS, Fenton TR, Sauve RS (2006) Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database Syst Rev CD003959

  68. Senterre T, Rigo J (2013) Update on nutritional management of the premature infants. P Belg Roy Acad Med 2:164–178

    Google Scholar 

  69. Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM (1998) A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 68:72–81

    CAS  PubMed  Google Scholar 

  70. Suryawan A, Orellana RA, Nguyen HV, Jeyapalan AS, Fleming JR, Davis TA (2007) Activation by insulin and amino acids of signaling components leading to translation initiation in skeletal muscle of neonatal pigs is developmentally regulated. Am J Physiol Endocrinol Metab 293:E1597–E1605

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  71. Suryawan A, Jeyapalan AS, Orellana RA, Wilson FA, Nguyen HV, Davis TA (2008) Leucine stimulates protein synthesis in skeletal muscle of the neonatal pig by enhancing mTORC1 activation. Am J Physiol Endocrinol Metab 295:E868–E875

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  72. Suryawan A, Torrazza RM, Gazzaneo MC, Orellana RA, Fiorotto ML, El-Kadi SW, Srivastava N, Nguyen HV, Davis TA (2012) Enteral leucine supplementation increases protein synthesis in skeletal and cardiac muscles and visceral tissues of neonatal pigs through mTORC1-dependent pathways. Pediatr Res 71:324–331

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  73. Tessari P, Inchiostro S, Biolo G, Trevisan R, Fantin G, Marescotti MC, Iori E, Tiengo A, Crepaldi G (1987) Differential effects of hyperinsulinemia and hyperaminoacidemia on leucine-carbon metabolism in vivo. Evidence for distinct mechanisms in regulation of net amino acid deposition. J Clin Invest 79:1062–1069

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  74. Thureen PJ, Hay WW (2001) Early aggressive nutrition in preterm infants. Semin Neonatol 6:403–415

    CAS  PubMed  Article  Google Scholar 

  75. Thureen PJ, Melara D, Fennessey PV, Hay WW (2003) Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr Res 53:24–32

    CAS  PubMed  Article  Google Scholar 

  76. Tischler ME, Desautels M, Goldberg AL (1982) Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J Biol Chem 257:1613–1621

    CAS  PubMed  Google Scholar 

  77. Torraza RM, Suryawan A, Gazzaneo MC, Orellana RA, Frank JW, Nguyen HV, Fiorotto ML, El-Kadi S, Davis TA (2010) Leucine supplementation of a low-protein meal increases skeletal muscle and visceral tissue protein synthesis in neonatal pigs by stimulating mTOR-dependent translation initiation. J Nutr 140:2145–2152

    Article  Google Scholar 

  78. Van Koevering M, Nissen S (1992) Oxidation of leucine and α-ketoisocaproate to β-hydroxy-β-methylbutyrate in vivo. Am J Physiol Endocrinol Metab 262:E27–E31

    Google Scholar 

  79. Volpi E, Kobayashi H, Sheffield-Moore M, Mittendorfer B, Wolfe RR (2003) Essential amino acids are primarily responsible for the amino acid stimulation of muscle protein anabolism in healthy elderly adults. Am J Clin Nutr 78:250–258

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Watt PW, Corbett ME, Rennie MJ (1992) Stimulation of protein synthesis in pig skeletal muscle by infusion of amino acids during constant insulin availability. Am J Physiol Endocrinol Metab 263:E453–E460

    CAS  Google Scholar 

  81. Wheatley SM, El-Kadi SW, Suryawan A, Boutry C, Orellana RA, Nguyen HV, Davis SR, Davis TA (2014) Protein synthesis in skeletal muscle of neonatal pigs is enhanced by administration of β-hydroxy-β-methylbutyrate. Am J Physiol Endocrinol Metab 306:E91–E99

    CAS  PubMed  Article  Google Scholar 

  82. Wilson FA, Suryawan A, Orellana RA, Kimball SR, Gazzaneo MC, Nguyen HV, Fiorotto ML, Davis TA (2009) Feeding rapidly stimulates protein synthesis in skeletal muscle of neonatal pigs by enhancing translation initiation. J Nutr 139:1873–1880

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  83. Wilson FA, Suryawan A, Gazzaneo MC, Orellana RA, Nguyen HV, Davis TA (2010) Stimulation of muscle protein synthesis by prolonged parenteral infusion of leucine is dependent on amino acid availability in neonatal pigs. J Nutr 140:264–270

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  84. Witard OC, Jackman SR, Breen L, Smith K, Selby A, Tipton KD (2014) Myofibrillar muscle protein synthesis rates subsequent to a meal in response to increasing doses of whey protein at rest and after resistance exercise. Am J Clin Nutr 99:86–95

    CAS  PubMed  Article  Google Scholar 

  85. Wray-Cahen D, Nguyen HV, Burrin DG, Beckett PR, Fiorotto ML, Reeds PJ, Wester TJ, Davis TA (1998) Response of skeletal muscle protein synthesis to insulin in suckling pigs decreases with development. Am J Physiol Endocrinol Metab 275:E602–E609

    CAS  Google Scholar 

  86. Wu G, Wu Z, Dai Z, Yang Y, Wang W, Liu C, Wang B, Wang J, Yin Y (2013) Dietary requirements of “nutritionally non-essential amino acids” by animals and humans. Amino Acids 44:1107–1113

    CAS  PubMed  Article  Google Scholar 

  87. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484

    CAS  PubMed  Article  Google Scholar 

  88. Yajnik CS (2004) Obesity epidemic in India: intrauterine origins? Proc Nutr Soc 63:387–396

    CAS  PubMed  Article  Google Scholar 

  89. Yin Y, Yao K, Liu Z, Gong M, Ruan Z, Den D, Tan B, Liu Z, Wu G (2010) Supplementing l-leucine to a low-protein diet increases tissue protein synthesis in weanling pigs. Amino Acids 39:1477–1486

    CAS  PubMed  Article  Google Scholar 

  90. Zanchi NE, Gerlinger-Romero F, Guimaraes-Ferreira L, de SiqueiraFilho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (2010) HMB supplementation: clinical and athletic performance-related effects and mechanisms of action. Amino Acids 40:1015–1025

    PubMed  Article  Google Scholar 

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Acknowledgments

The work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants AR-044474 (Davis) and AR-46308 (Fiorotto), National Institute of Child Health and Human Development HD-072891 (Davis), United States Department of Agriculture National Institute of Agriculture grant 2013-67015-20438 (Davis), and by the USDA/ARS under Cooperative Agreement no. 6250-510000-055 (Davis). This work is a publication of the USDA, Agricultural Research Service (USDA/ARS) Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX. The contents of this publication do not necessarily reflect the views or politics of the USDA, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government.

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The authors have no conflicts of interests.

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Correspondence to Teresa A. Davis.

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Columbus, D.A., Fiorotto, M.L. & Davis, T.A. Leucine is a major regulator of muscle protein synthesis in neonates. Amino Acids 47, 259–270 (2015). https://doi.org/10.1007/s00726-014-1866-0

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Keywords

  • Amino acids
  • Leucine
  • Low birth weight
  • mTOR
  • Neonatal
  • Protein synthesis