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.

Fig. 1

Fractional protein synthesis rates in longissimusdorsi muscle of 7- and 26-d-old neonatal pigs in which saline, insulin, amino acids (AA), or both amino acids and insulin were infused during a pancreatic clamp. Euglycemia was maintained at the fasting level. *Significantly different than control within an age group (P< 0.05). Adapted from Davis et al. (2002) with permission.

Fig. 2

Fractional protein synthesis rates in longissimusdorsi muscle of neonatal pigs at different levels of insulin and amino acids. *Significantly different than previous insulin level within same amino acid level (P < 0.05). †Significantly different than 500 nmol/ml branched-chain amino acids (BCAA) within same insulin level (P< 0.05). Adapted from O’Connor et al (2003) with permission.

Fig. 3

Regulation of protein synthesis through the mTOR signaling pathway by amino acids and insulin. Insulin binds to its receptor and activates insulin receptor substrate-1 (IRS-1) which in turn activates phosphoinositide-3 kinase (PI3K), phosphoinositide-dependent kinase (PDK), and Akt. Activation of Akt removes the inhibition of mTOR by the tuberous sclerosis complex 1 and 2 (TSC 1/2). Both amino acids and insulin activatemTOR, which results in inactivation of the eukaryotic initiation factor repressor 4E-binding protein 1 (4EBP1), release of eukaryotic initiation factor (eIF) 4E, and formation of the active eIF4E·eIF4G complex. mTOR also activates ribosomal protein S6 kinase 1 (S6K1) which in turn activates ribosomal protein S6 (S6) allowing recruitment of the 60S and 40S ribosomal subunits. Phosphorylation of S6 and formation of the active eIF4E·eIF4G complex stimulate translation initiation and protein synthesis.

Fig. 4

Changes in phosphorylation of mTOR^Ser2448 (A), ribosomal protein S6^Ser235/236 (B), and 4EBP1^Thr70 (C) over 240 min in longissimusdorsi muscle of neonatal pigs following a meal providing one-sixth of their daily requirements. Means without a common letter differ (P< 0.05).Adapted from Wilson et al. (2009) with permission.

Fig. 5

Fractional protein synthesis rates in longissimusdorsi muscle of fasted neonatal pigs intravenously infused with saline, leucine, isoleucine, or valine. Means without a common letter differ (P < 0.05).Adapted from Escobar et al. (2006) with permission.

Fig. 6

Fractional protein synthesis rates(A),phosphorylation of S6K1^Thr389 (B) and 4EBP1^Thr46 (C), and formation of the active eIF4G·eIF4E complex (D) in longissimusdorsi muscle of fasted neonatal pigs intravenously infused with 0, 20, 100, or 400 μmol/kg^/hHMB for 1 h. Means without a common letter differ (P< 0.05). Adapted from Wheatley et al. (2014) with permission.

Fig. 7

Fractional protein synthesis rates (A), phosphorylation of S6K1^Thr389 (B) and 4EBP1^Thr46 (C), and formation of the active eIF4G·eIF4E complex (D) in longissimusdorsi muscle of neonatal pigscontinuously fed (CON), continuously fed and pulsed with leucine (CON+LEU), or bolus fed (BOL). Means without a common letter differ (P< 0.05). Adapted from Boutry et al. (2013) with permission.