Intermittent Bolus Compared with Continuous Feeding Promotes Higher Activation of Insulin and Amino Acid Signaling to Protein Synthesis in Skeletal Muscle of Neonatal Pigs

Abstract Objectives Our recent study in a piglet model of the human neonate born at full term showed that intermittent bolus feeding promotes greater rates of protein synthesis in skeletal muscle than continuous feeding, leading to an increase in lean growth. This enhanced rate of muscle protein synthesis with intermittent bolus feeding is associated with an increased activation of mTORC1-dependent translation initiation. However, the mechanism underlying this response is unknown. In this study, we aimed to identify the insulin and/or amino acid signaling components involved in the enhanced stimulation of lean growth by intermittent bolus compared to continuous feeding in term-born pigs. Methods Term piglets (2–3 d old) were fed for 21 d an equal amount (240 ml/kg body weight [BW]/d) of sow milk replacer containing 12.8 g protein and 175 kcal/kg BW/d. Feedings were administered by gastrostomy tube either as intermittent bolus meals every 4 h (INT) or by continuous infusion (CON). After 21 d, gastrocnemius muscle was collected from CON, INT-0 (before a meal) and INT-60 (60 min after a meal) groups. Upstream and downstream insulin and amino acid signaling components of relevance to mTORC1 activation and protein translation were measured. Results Phosphorylation of AKT and TCS2 was greater in INT-60 than in INT-0 and CON groups (P < 0.05). There was no significant difference between CON and INT groups in the phosphorylation of ERK 1/2 and AMPK. The association of Sestrin2, a leucine sensor, with GATOR2 was similar in CON and INT-0 but was lower in INT-60 (P < 0.05). The abundances of RagA-mTOR, RagC-mTOR, and Rheb-mTOR complexes were higher in INT-60 than in CON and INT-0 (P < 0.05). The phosphorylation of S6K1 and 4EBP1 was higher in INT-60 than CON and INT-0 groups (P < 0.05). Phosphorylation of eIF2alpha and eEF2 were not affected by treatments. Conclusions Our results demonstrate that, following a full-term birth, the enhanced rate of skeletal muscle protein synthesis and lean growth with intermittent bolus compared to continuous feeding is at least in part due to the enhanced activation of both insulin and amino acid signaling pathways leading to greater stimulation of translation initiation. Funding Sources NIH HD085573, USDA CRIS 6250-51000-055, NIH HD072891, USDA NIFA 2013-67015-20438.

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Intermittent Bolus Feeding Has a Greater Stimulatory Effect on Protein Synthesis in Skeletal Muscle than Continuous Feeding in Neonatal Pigs

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.327.3 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Maria C Gazzaneo ◽

Roberto Murgas Torrazza ◽

Agus Suryawan ◽

Renán A. Orellana ◽

Neeraj Srivastava ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Neonatal Pigs ◽

Intermittent Bolus ◽

Continuous Feeding

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Intermittent bolus feeding promotes greater lean growth than continuous feeding in a neonatal piglet model

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy133 ◽

2018 ◽

Vol 108 (4) ◽

pp. 830-841 ◽

Cited By ~ 8

Author(s):

Samer W El-Kadi ◽

Claire Boutry ◽

Agus Suryawan ◽

Maria C Gazzaneo ◽

Renán A Orellana ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Amino Acid ◽

Muscle Mass ◽

Initiation Factor ◽

Feeding Frequency ◽

Orogastric Tube ◽

Intermittent Bolus ◽

Lean Growth ◽

Continuous Feeding

Abstract Background Orogastric tube feeding is indicated in neonates with an impaired ability to ingest food normally and can be administered with an intermittent bolus or continuous feeding schedule. Objectives The objectives were to 1) compare the long-term effect of continuous with intermittent feeding on growth using the newborn pig as a model, 2) determine whether feeding frequency alters lean tissue and fat mass gain, and 3) identify the signaling mechanisms by which protein deposition is controlled in skeletal muscle in response to feeding frequency. Design Neonatal pigs were fed the same amount of a balanced formula by orogastric tube either as an intermittent bolus meal every 4 h (INT) or as a continuous infusion (CON). Body composition was assessed at the start and end of the study by dual-energy X-ray absorptiometry, and hormone and substrate profiles, muscle mass, protein synthesis, and indexes of nutrient and insulin signaling were measured after 21 d. Results Body weight, lean mass, spine length, and skeletal muscle mass were greater in the INT group than in the CON group. Skeletal muscle fractional protein synthesis rates were greater in the INT group after a meal than in the CON group and were associated with higher circulating branched-chain amino acid and insulin concentrations. Skeletal muscle protein kinase B (PKB) and ribosomal protein S6 kinase phosphorylation and eukaryotic initiation factor (eIF) 4E–eIF4G complex formation were higher, whereas eIF2α phosphorylation was lower in the INT group than in the CON group, indicating enhanced activation of insulin and amino acid signaling to translation initiation. Conclusions These results suggest that when neonates are fed the same amounts of nutrients as intermittent meals rather than continuously there is greater lean growth. This response can be ascribed, in part, to the pulsatile pattern of amino acids, insulin, or both induced by INT, which enables the responsiveness of anabolic pathways to feeding to be sustained chronically in skeletal muscle.

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356 Meal feeding compared with continuous feeding enhances insulin and amino acid signaling to translation initiation in skeletal muscle of pigs

Journal of Animal Science ◽

10.1093/jas/skz258.261 ◽

2019 ◽

Vol 97 (Supplement_3) ◽

pp. 127-128

Author(s):

Teresa A Davis ◽

Samer El-Kadi ◽

Agus Suryawan ◽

Marta Fiorotto

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Amino Acid ◽

Translation Initiation ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Lean Growth ◽

Continuous Feeding ◽

Meal Feeding ◽

Amino Acid Signaling

Abstract Objectives: Meal feeding enhances skeletal muscle protein synthesis and lean growth more than continuous feeding in piglets. This enhanced muscle protein synthesis with meal feeding is associated with increased activation of mTORC1-dependent translation initiation. The mechanism underlying this response is unknown. We aimed to identify insulin and amino acid signaling components involved in the enhanced lean growth that results from meal feeding vs. continuous feeding in term-born pigs. Methods: Newborn piglets were fed for 21 d an equal amount of sow milk replacer (12.8 g protein and 155 kcal/(kg BW.d)) by gastrostomy tube either as intermittent bolus meals every 4 h (MEAL) or by continuous infusion (CON). After 21 d, gastrocnemius muscle was collected from CON, and before (MEAL-0) or 60 min after a meal (MEAL-60). Components of the insulin and amino acid signaling pathways up- and downstream of mTORC1 that regulate protein translation were measured. Results: Phosphorylation of AKT and TCS2 was greater in MEAL-60 than in MEAL-0 and CON (P < 0.05). The association of Sestrin2 with GATOR2 was similar in CON and MEAL-0 but was lower in MEAL-60 (P < 0.05). The abundances of RagA-mTOR, RagC-mTOR, and Rheb-mTOR, but not CASTOR1-GATOR2, complexes were higher in MEAL-60 than in CON and MEAL-0 (P < 0.05). The phosphorylation of S6K1 and 4EBP1 was higher in MEAL-60 than CON and MEAL-0 (P < 0.05). The abundances of Sestrin2, GATOR2, CASTOR1, RagA, RagC, and Rheb and the phosphorylation of eIF2alpha, eEF2, ERK1/2 and AMPK were unaffected by treatments. Conclusions: Our results demonstrate that the enhanced rate of skeletal muscle protein synthesis and lean growth with meal feeding compared with continuous feeding are due to the enhanced activation of both insulin and amino acid signaling pathways that result in the greater stimulation of translation initiation. Support: NIH HD085573, USDA CRIS 6250-51000-055, NIH HD072891, USDA NIFA 2013-67015-20438.

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Intermittent Bolus Feeding Has a Greater Stimulatory Effect on Protein Synthesis in Skeletal Muscle Than Continuous Feeding in Neonatal Pigs

Journal of Nutrition ◽

10.3945/jn.111.147520 ◽

2011 ◽

Vol 141 (12) ◽

pp. 2152-2158 ◽

Cited By ~ 34

Author(s):

María C. Gazzaneo ◽

Agus Suryawan ◽

Renán A. Orellana ◽

Roberto Murgas Torrazza ◽

Samer W. El-Kadi ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Neonatal Pigs ◽

Intermittent Bolus ◽

Continuous Feeding

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Supplementation with a leucine pulse during continuous feeding stimulates protein synthesis and suppresses protein degradation pathways in skeletal muscle of neonatal pigs

Energy and protein metabolism and nutrition in sustainable animal production ◽

10.3920/978-90-8686-781-3_151 ◽

2013 ◽

pp. 415-416

Author(s):

C. Boutry ◽

S. W. El-Kadi ◽

A. Suryawan ◽

S. M. Wheatley ◽

R. A. Orellana ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Protein Degradation ◽

Degradation Pathways ◽

Neonatal Pigs ◽

Continuous Feeding

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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 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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Continuous Feeding Does Not Blunt Skeletal Muscle Protein Synthesis and Lean Growth Compared to Intermittent Bolus Feeding in the Preterm Piglet (OR26-06-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz033.or26-06-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Marko Rudar ◽

Jane Naberhuis ◽

Hanh Nguyen ◽

Agus Suryawan ◽

Candace Style ◽

...

Keyword(s):

Skeletal Muscle ◽

Body Weight ◽

Protein Synthesis ◽

Translation Initiation ◽

Muscle Protein ◽

Feeding Strategies ◽

Intermittent Bolus ◽

Lean Growth ◽

Continuous Feeding ◽

The Impact

Abstract Objectives Refining early feeding strategies for premature infants is essential for mitigating adverse outcomes of prematurity. In neonatal term piglets, continuous feeding blunts growth compared to intermittent bolus feeding. Our objective was to determine the impact of feeding modality on lean growth in preterm pigs. We hypothesized that intermittent bolus feeding can mitigate low lean growth rates in preterm neonates compared to continuous feeding. Methods Pigs obtained by C-section (105 d gestation; 952 ± 205 g body weight) were fitted with an umbilical artery catheter (later replaced with jugular vein catheter) and an orogastric tube for parenteral and enteral nutrition, respectively. Pigs were assigned to continuous (CONT; 7.5 mL/[kg·h]) or intermittent bolus (INT; 30 mL/kg every 4 h over 15 min) feeding for 21 d. Pigs initially received parenteral nutrition and were advanced to full oral feeds over 6 d (220 kcal/kg and 16 g/kg protein per day). Body composition (by DXA), plasma insulin, and skeletal muscle anabolic signaling and fractional protein synthesis rates (PS; L-[ring-2H5]phenylalanine) were determined in INT pigs in the postabsorptive (before a meal, INT-PA; n = 13) and postprandial (after a meal, INT-PP; n = 16) states and in CONT pigs (n = 14). Results Body weight gain, lean mass, and fat mass did not differ between INT and CONT pigs. Insulin was lower before feeding for INT pigs than CONT pigs (P < 0.05). Insulin increased with feeding for INT pigs and exceeded that of CONT pigs at 30 and 60 min (P < 0.01) before returning to baseline levels at 240 min. In the longissimus dorsi (LD), gastrocnemius, and soleus muscles, the abundance of the eIF4E·eIF4G complex, which is required for translation initiation, was greater in INT-PP and CONT pigs than INT-PA pigs (P < 0.01), but did not differ between INT-PP and CONT pigs. PS in the LD muscle was greater in INT-PP pigs than INT-PA pigs (P < 0.01), but did not differ between INT-PP and CONT pigs. Conclusions Continuous feeding does not blunt translation initiation and protein synthesis in skeletal muscle compared to intermittent bolus feeding in preterm piglets. The resulting absence of enhanced lean growth with intermittent bolus compared to continuous feeding contrasts with term piglets and may be a consequence of prematurity. Funding Sources USDA CRIS 6250-51000-055, NIH HD072891, and USDA NIFA 2013-67015-20438.

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