Intermittent bolus feeding does not enhance protein synthesis, myonuclear accretion, or lean growth more than continuous feeding in a premature piglet model

Optimizing enteral nutrition for premature infants may help mitigate extrauterine growth restriction and adverse chronic health outcomes. Previously, we showed in neonatal pigs born at term that lean growth is enhanced by intermittent bolus compared to continuous feeding. The objective was to determine if prematurity impacts how body composition, muscle protein synthesis, and myonuclear accretion respond to feeding modality. Following preterm delivery, pigs were fed equivalent amounts of formula delivered either as intermittent boluses (INT; n = 30) or continuously (CONT; n = 14) for 21 days. Body composition was measured by DXA and muscle growth was assessed by morphometry, myonuclear accretion, and satellite cell abundance. Tissue anabolic signaling and fractional protein synthesis rates were determined in INT pigs in postabsorptive (INT-PA) and postprandial (INT-PP) states and in CONT pigs. Body weight gain and composition did not differ between INT and CONT pigs. Longissimus dorsi (LD) protein synthesis was 34% greater in INT-PP than INT-PA pigs (P < 0.05) but was not different between INT-PP and CONT pigs. Phosphorylation of 4EBP1 and S6K1 and eIF4E·eIF4G abundance in LD paralleled changes in LD protein synthesis. Satellite cell abundance, myonuclear accretion, and fiber cross-sectional area in LD did not differ between groups. These results suggest that, unlike pigs born at term, intermittent bolus feeding does not enhance lean growth more than continuous feeding in pigs born preterm. Premature birth attenuates the capacity of skeletal muscle to respond to cyclical surges in insulin and amino acids with intermittent feeding in early postnatal life.

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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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Intermittent Bolus Compared with Continuous Feeding Enhances Insulin and Amino Acid Signaling to Translation Initiation in Skeletal Muscle of Pigs Born at Term (P08-071-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz044.p08-071-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Agus Suryawan ◽

Samer El-Kadi ◽

Hanh Nguyen ◽

Marta Fiorotto ◽

Teresa Davis

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Amino Acid ◽

Translation Initiation ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Intermittent Bolus ◽

Lean Growth ◽

Continuous Feeding ◽

Amino Acid Signaling

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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Anabolic signaling and protein deposition are enhanced by intermittent compared with continuous feeding in skeletal muscle of neonates

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00516.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. E674-E686 ◽

Cited By ~ 36

Author(s):

Samer W. El-Kadi ◽

Agus Suryawan ◽

Maria C. Gazzaneo ◽

Neeraj Srivastava ◽

Renán A. Orellana ◽

...

Keyword(s):

Protein Synthesis ◽

Protein Degradation ◽

Muscle Protein ◽

Mrna Translation ◽

Initiation Factor ◽

Whole Body ◽

Signaling Proteins ◽

Protein Deposition ◽

Intermittent Bolus ◽

Continuous Feeding

Orogastric tube feeding is indicated for neonates with impaired ability to ingest and can be administered by intermittent bolus or continuous schedule. Our aim was to determine whether feeding modalities affect muscle protein deposition and to identify mechanisms involved. Neonatal pigs were overnight fasted (FAS) or fed the same amount of food continuously (CON) or intermittently (INT; 7 × 4 h meals) for 29 h. For 8 h, between hours 20 and 28, pigs were infused with [2H5]phenylalanine and [2H2]tyrosine, and amino acid (AA) net balances were measured across the hindquarters. Insulin, branched-chain AA, phenylalanine, and tyrosine arterial concentrations and whole body phenylalanine and tyrosine fluxes were greater for INT after the meal than for CON or FAS. The activation of signaling proteins leading to initiation of mRNA translation, including eukaryotic initiation factor (eIF)4E·eIF4G complex formation in muscle, was enhanced by INT compared with CON feeding or FAS. Signaling proteins of protein degradation were not affected by feeding modalities except for microtubule-associated protein light chain 3-II, which was highest in the FAS. Across the hindquarters, AA net removal increased for INT but not for CON or FAS, with protein deposition greater for INT. This was because protein synthesis increased following feeding for INT but remained unchanged for CON and FAS, whereas there was no change in protein degradation across any dietary treatment. These results suggest that muscle protein accretion in neonates is enhanced with intermittent bolus to a greater extent than continuous feeding, mainly by increased protein synthesis.

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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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Viscera and muscle protein synthesis in neonatal pigs is increased more by intermittent bolus than by continuous feeding

Pediatric Research ◽

10.1038/pr.2013.89 ◽

2013 ◽

Vol 74 (2) ◽

pp. 154-162 ◽

Cited By ~ 9

Author(s):

Samer W. El-Kadi ◽

María C. Gazzaneo ◽

Agus Suryawan ◽

Renán A. Orellana ◽

Roberto Murgas Torrazza ◽

...

Keyword(s):

Protein Synthesis ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Neonatal Pigs ◽

Intermittent Bolus ◽

Continuous Feeding

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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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Chronic effects of β2 agonists on body composition and protein synthesis in the rat

Bioscience Reports ◽

10.1007/bf01120827 ◽

1984 ◽

Vol 4 (1) ◽

pp. 83-91 ◽

Cited By ~ 220

Author(s):

P. W. Emery ◽

N. J. Rothwell ◽

M. J. Stock ◽

P. D. Winter

Keyword(s):

Protein Synthesis ◽

Muscle Protein ◽

Binding Capacity ◽

Body Weight Gain ◽

Muscle Protein Synthesis ◽

Body Protein ◽

Fractional Rate ◽

Brown Adipose ◽

Β2 Agonists

Chronic treatment of rats with the β2-adrenergic agonists clenbuterol and fenoterol over 16–19 d raised energy intake, expenditure, and body weight gain but did not affect fat or energy deposition, and body protein gain was increased by 50 and 18%, respectively. Both drugs increased the protein content and mitochondrial GDP-binding capacity of brown adipose tissue. Clenbuterol did not affect plasma insulin, growth hormone, or triiodothyronine levels, although insulin levels were reduced by fenoterol. Both drugs caused hypertrophy of skeletal muscle (gastrocnemius), and muscle protein synthesis in vivo (fractional rate) was elevated by 34 and 26% in clenbuterol and fenoteroltreated rats, respectively.

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Effect of Aerobic Exercise Training and Essential Amino Acid Supplementation for 24 Weeks on Physical Function, Body Composition, and Muscle Metabolism in Healthy, Independent Older Adults: A Randomized Clinical Trial

The Journals of Gerontology Series A ◽

10.1093/gerona/gly109 ◽

2018 ◽

Vol 74 (10) ◽

pp. 1598-1604 ◽

Cited By ~ 11

Author(s):

Melissa M Markofski ◽

Kristofer Jennings ◽

Kyle L Timmerman ◽

Jared M Dickinson ◽

Christopher S Fry ◽

...

Keyword(s):

Older Adults ◽

Clinical Trial ◽

Body Composition ◽

Protein Synthesis ◽

Muscle Strength ◽

Randomized Clinical Trial ◽

Walking Speed ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Before And After

Abstract Background Essential amino acids (EAA) and aerobic exercise (AE) acutely and independently stimulate skeletal muscle protein anabolism in older adults. Objective In this Phase 1, double-blind, placebo-controlled, randomized clinical trial, we determined if chronic EAA supplementation, AE training, or a combination of the two interventions could improve muscle mass and function by stimulating muscle protein synthesis. Methods We phone-screened 971, enrolled 109, and randomized 50 independent, low-active, nonfrail, and nondiabetic older adults (age 72 ± 1 years). We used a 2 × 2 factorial design. The interventions were: daily nutritional supplementation (15 g EAA or placebo) and physical activity (supervised AE training 3 days/week or monitored habitual activity) for 24 weeks. Muscle strength, physical function, body composition, and muscle protein synthesis were measured before and after the 24-week intervention. Results Forty-five subjects completed the 24-week intervention. VO2peak and walking speed increased (p < .05) in both AE groups, irrespective of supplementation type, but muscle strength increased only in the EAA + AE group (p < .05). EAA supplementation acutely increased (p < .05) muscle protein synthesis from basal both before and after the intervention, with a larger increase in the EAA + AE group after the intervention. Total and regional lean body mass did not change significantly with any intervention. Conclusions In nonfrail, independent, healthy older adults AE training increased walking speed and aerobic fitness, and, when combined with EAA supplementation, it also increased muscle strength and EAA-stimulated muscle protein synthesis. These increases occurred without improvements in muscle mass.

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