184 Supplementation with Leucine and the Leucine Metabolite, Beta-hydroxy-beta-methylbutyrate, Stimulates Muscle Protein Synthesis in Neonatal Pigs via Different Signaling Mechanisms.

In neonatal animals, feeding stimulates skeletal muscle protein synthesis, a response that declines with development. Both the magnitude of the feeding response and its developmental decline can be reproduced by insulin infusion, suggesting that an altered responsiveness to insulin is a primary determinant of the developmental decline in the stimulation of protein synthesis by feeding. In this study, 7- and 26-day-old pigs were either fasted overnight or fed porcine milk after an overnight fast. We examined the abundance and degree of tyrosine phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and IRS-2 in skeletal muscle and, for comparison, liver. We also evaluated the association of IRS-1 and IRS-2 with phosphatidylinositol 3-kinase (PI 3-kinase). The abundance of IR protein in muscle was twofold higher at 7 than at 26 days, but IRS-1 and IRS-2 abundances were similar in muscle of 7- and 26-day-old pigs. The feeding-induced phosphorylations were greater at 7 than at 26 days of age for IR (28- vs. 13-fold), IRS-1 (14- vs. 8-fold), and IRS-2 (21- vs. 12-fold) in muscle. The associations of IRS-1 and IRS-2 with PI 3-kinase were also increased by refeeding to a greater extent at 7 than at 26 days (9- vs. 5-fold and 6- vs. 4-fold, respectively). In liver, the abundance of IR, IRS-1, and IRS-2 was similar at 7 and 26 days of age. Feeding increased the activation of IR, IRS-1, IRS-2, and PI 3-kinase in liver only twofold, and these responses were unaffected by age. Thus our findings demonstrate that the feeding-induced activation of IR, IRS-1, IRS-2, and PI 3-kinase in skeletal muscle decreases with development. Further study is needed to ascertain whether the developmental decline in the feeding-induced activation of early insulin-signaling components contributes to the developmental decline in translation initiation in skeletal muscle.

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Physiological rise in plasma leucine stimulates muscle protein synthesis in neonatal pigs by enhancing translation initiation factor activation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00510.2004 ◽

2005 ◽

Vol 288 (5) ◽

pp. E914-E921 ◽

Cited By ~ 93

Author(s):

Jeffery Escobar ◽

Jason W. Frank ◽

Agus Suryawan ◽

Hanh V. Nguyen ◽

Scot R. Kimball ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Amino Acid ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Neonatal Pigs ◽

Plasma Leucine

Protein synthesis in skeletal muscle of adult rats increases in response to oral gavage of supraphysiological doses of leucine. However, the effect on protein synthesis of a physiological rise in plasma leucine has not been investigated in neonates, an anabolic population highly sensitive to amino acids and insulin. Therefore, in the current study, fasted pigs were infused intra-arterially with leucine (0, 200, or 400 μmol·kg−1·h−1), and protein synthesis was measured after 60 or 120 min. Protein synthesis was increased in muscle, but not in liver, at 60 min. At 120 min, however, protein synthesis returned to baseline levels in muscle but was reduced below baseline values in liver. The increase in protein synthesis in muscle was associated with increased plasma leucine of 1.5- to 3-fold and no change in plasma insulin. Leucine infusion for 120 min reduced plasma essential amino acid levels. Phosphorylation of eukaryotic initiation factor (eIF)-4E-binding protein-1 (4E-BP1), ribosomal protein (rp) S6 kinase, and rpS6 was increased, and the amount of eIF4E associated with its repressor 4E-BP1 was reduced after 60 and 120 min of leucine infusion. No change in these biomarkers of mRNA translation was observed in liver. Thus a physiological increase in plasma leucine stimulates protein synthesis in skeletal muscle of neonatal pigs in association with increased eIF4E availability for eIF4F assembly. This response appears to be insulin independent, substrate dependent, and tissue specific. The results suggest that the branched-chain amino acid leucine can act as a nutrient signal to stimulate protein synthesis in skeletal muscle of neonates.

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Leucine and α-Ketoisocaproic Acid, but Not Norleucine, Stimulate Skeletal Muscle Protein Synthesis in Neonatal Pigs

Journal of Nutrition ◽

10.3945/jn.110.123042 ◽

2010 ◽

Vol 140 (8) ◽

pp. 1418-1424 ◽

Cited By ~ 55

Author(s):

Jeffery Escobar ◽

Jason W. Frank ◽

Agus Suryawan ◽

Hanh V. Nguyen ◽

Cynthia G. Van Horn ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Skeletal Muscle Protein ◽

Neonatal Pigs ◽

Skeletal Muscle Protein Synthesis

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Leucine Pulse Increases Skeletal Muscle Protein Synthesis during Continuous Feeding in Neonatal Pigs

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.265.5 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

Claire Boutry ◽

Agus Suryawan ◽

Samer W El-Kadi ◽

Scott M Wheatley ◽

Renan A Orellana ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Skeletal Muscle Protein ◽

Neonatal Pigs ◽

Skeletal Muscle Protein Synthesis ◽

Continuous Feeding

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Chronic Enteral Leucine Supplementation of a Low Protein Diet Increases Skeletal Muscle Protein Synthesis in Neonatal Pigs by Stimulating mTOR‐Dependent Translation Initiation

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.327.4 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Roberto Murgas Torrazza ◽

Agus Suryawan ◽

Maria C. Gazzaneo ◽

Renan A. Orellana ◽

Hanh V. Nguyen ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Translation Initiation ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Skeletal Muscle Protein ◽

Leucine Supplementation ◽

Neonatal Pigs ◽

Low Protein ◽

Skeletal Muscle Protein Synthesis

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Downregulated Translation Initiation Signaling Predisposes Low-Birth-Weight Neonatal Pigs to Slower Rates of Muscle Protein Synthesis

Frontiers in Physiology ◽

10.3389/fphys.2017.00482 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 3

Author(s):

Ying Chen ◽

Sydney R. McCauley ◽

Sally E. Johnson ◽

Robert P. Rhoads ◽

Samer W. El-Kadi

Keyword(s):

Protein Synthesis ◽

Birth Weight ◽

Low Birth Weight ◽

Translation Initiation ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Neonatal Pigs

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Modulation of muscle protein synthesis by insulin is maintained during neonatal endotoxemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00595.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. E159-E166 ◽

Cited By ~ 16

Author(s):

Renan A. Orellana ◽

Pamela M. J. O'Connor ◽

Jill A. Bush ◽

Agus Suryawan ◽

M. Carole Thivierge ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Amino Acids ◽

Protein Synthesis ◽

Gastrocnemius Muscle ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Liver Protein ◽

Fasting Insulin ◽

Neonatal Pigs

Sepsis promotes insulin resistance and reduces protein synthesis in skeletal muscle of adults. The effect of sepsis on insulin-stimulated muscle protein synthesis has not been determined in neonates, a highly anabolic population that is uniquely sensitive to insulin. Overnight fasted neonatal pigs were infused for 8 h with endotoxin [lipopolysaccharide (LPS), 0 and 10 μg·kg−1·h−1]. Glucose and amino acids were maintained at fasting levels, insulin was clamped at either fasting or fed (2 or 10 μU/ml) levels, and fractional protein synthesis rates were determined at the end of the infusion. LPS infusion induced a septic-like state, as indicated by a sustained elevation in body temperature, heart rate, and cortisol. At fasting insulin levels, LPS reduced fractional protein synthesis rates in gastrocnemius muscle (−26%) but had no effect on the masseter and heart. By contrast, LPS stimulated liver protein synthesis (+28%). Increasing insulin to fed levels accelerated protein synthesis rates in gastrocnemius (controls by +38%, LPS by +60%), masseter (controls by +50%, LPS by +43%), heart (controls by +34%, LPS by +40%), and diaphragm (controls by +54%, LPS by +29%), and the response to insulin was similar in LPS and controls. Insulin did not alter protein synthesis in liver, kidney, or jejunum in either group. These findings suggest that acute endotoxemia lowers basal fasting muscle protein synthesis in neonates but does not alter the response of protein synthesis to insulin.

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Leucine pulses enhance skeletal muscle protein synthesis during continuous feeding in neonatal pigs

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00135.2013 ◽

2013 ◽

Vol 305 (5) ◽

pp. E620-E631 ◽

Cited By ~ 32

Author(s):

Claire Boutry ◽

Samer W. El-Kadi ◽

Agus Suryawan ◽

Scott M. Wheatley ◽

Renán A. Orellana ◽

...

Keyword(s):

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Essential Amino Acids ◽

Oral Feeding ◽

Skeletal Muscle Protein ◽

Orogastric Tube ◽

Neonatal Piglets ◽

Neonatal Pigs ◽

Continuous Feeding

Infants unable to maintain oral feeding can be nourished by orogastric tube. We have shown that orogastric continuous feeding restricts muscle protein synthesis compared with intermittent bolus feeding in neonatal pigs. To determine whether leucine infusion can be used to enhance protein synthesis during continuous feeding, neonatal piglets received the same amount of formula enterally by orogastric tube for 25.25 h continuously (CON) with or without LEU or intermittently by bolus every 4 h (BOL). For the CON+LEU group, leucine pulses were administered parenterally (800 μmol·kg−1·h−1) every 4 h. Insulin and glucose concentrations increased after the BOL meal and were unchanged in groups fed continuously. LEU infusion during CON feeding increased plasma leucine after the leucine pulse and decreased essential amino acids compared with CON feeding. Protein synthesis in longissimus dorsi (LD), gastrocnemius, and soleus muscles, but not liver or heart, were greater in CON+LEU and BOL than in the CON group. BOL feeding increased protein synthesis in the small intestine. Muscle S6K1 and 4E-BP1 phosphorylation and active eIF4E·eIF4G complex formation were higher in CON+LEU and BOL than in CON but AMPKα, eIF2α, and eEF2 phosphorylation were unchanged. LC3-II-to-total LC3 ratio was lower in CON+LEU and BOL than in CON, but there were no differences in atrogin-1 and MuRF-1 abundance and FoxO3 phosphorylation. In conclusion, administration of leucine pulses during continuous orogastric feeding in neonates increases muscle protein synthesis by stimulating translation initiation and may reduce protein degradation via the autophagy-lysosome, but not the ubiquitin-proteasome pathway.

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