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

Boutry, Claire; El‐Kadi, Samer W.; Suryawan, Agus; Wheatley, Scott M.; Orellana, Renán A.; Kimball, Scot R.; Nguyen, Hanh V.; Davis, Teresa A.

doi:10.1152/ajpendo.00135.2013

Cited by 50 publications

(68 citation statements)

References 80 publications

(113 reference statements)

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“…L‐Leu stimulates protein synthesis in muscle cells through at least two distinct mechanisms: by stimulation of mRNA translation initiation machinery13, 35 and by activation of intracellular signalling pathways linked to mTOR 6, 36, 37. The positive effects of L‐Leu supplementation on protein synthesis have been widely studied in situations where the subjects were either in deficient or fasting conditions,8, 11, 12, 13, 14, 15 and therefore under a catabolic stimulus.…”

Section: Discussionmentioning

confidence: 99%

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Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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BackgroundL‐Leu and its metabolite β‐hydroxy‐β‐methylbutyrate (HMB) stimulate muscle protein synthesis enhancing the phosphorylation of proteins that regulate anabolic signalling pathways. Alterations in these pathways are observed in many catabolic diseases, and HMB and L‐Leu have proven their anabolic effects in in vivo and in vitro models. The aim of this study was to compare the anabolic effects of L‐Leu and HMB in myotubes grown in the absence of any catabolic stimuli.MethodsStudies were conducted in vitro using rat L6 myotubes under normal growth conditions (non‐involving L‐Leu‐deprived conditions). Protein synthesis and mechanistic target of rapamycin signalling pathway were determined.ResultsOnly HMB was able to increase protein synthesis through a mechanism that involves the phosphorylation of the mechanistic target of rapamycin as well as its downstream elements, pS6 kinase, 4E binding protein‐1, and eIF4E. HMB was significantly more effective than L‐Leu in promoting these effects through an activation of protein kinase B/Akt. Because the conversion of L‐Leu to HMB is limited in muscle, L6 cells were transfected with a plasmid that codes for α‐keto isocaproate dioxygenase, the key enzyme involved in the catabolic conversion of α‐keto isocaproate into HMB. In these transfected cells, L‐Leu was able to promote protein synthesis and mechanistic target of rapamycin regulated pathway activation equally to HMB. Additionally, these effects of leucine were reverted to a normal state by mesotrione, a specific inhibitor of α‐keto isocaproate dioxygenase.ConclusionOur results suggest that HMB is an active L‐Leu metabolite able to maximize protein synthesis in skeletal muscle under conditions, in which no amino acid deprivation occurred. It may be proposed that supplementation with HMB may be very useful to stimulate protein synthesis in wasting conditions associated with chronic diseases, such as cancer or chronic heart failure.

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Section: Discussionmentioning

confidence: 99%

“…The positive effects of L‐Leu supplementation on protein synthesis have been widely studied in situations where the subjects were either in deficient or fasting conditions,8, 11, 12, 13, 14, 15 and therefore under a catabolic stimulus.…”

Section: Discussionmentioning

confidence: 99%

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Girón

Rienda

Salto

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

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“…Our laboratory has demonstrated that short-term administration of leucine provided either parenterally or enterally increases skeletal muscle protein synthesis in neonatal pigs, and this effect is associated with an increase in the activation of mTORC1 and its downstream targets (34,59). Recently, we showed that parenteral administration of leucine pulses every 4 h for 24 h during continuous orogastric feeding enhances protein synthesis by triggering the activation of mTORC1-regulated translation initiation in a pulsatile manner, similar to that which occurs with intermittent bolus feeding (8). The long-term effects of leucine have been studied largely for the maintenance of lean body mass in adults and for the treatment of muscle loss in the elderly (3), but its efficacy is still controversial because of contradictory results.…”

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confidence: 93%

Pulsatile delivery of a leucine supplement during long-term continuous enteral feeding enhances lean growth in term neonatal pigs

Boutry

El‐Kadi

Suryawan

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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TA. Pulsatile delivery of a leucine supplement during long-term continuous enteral feeding enhances lean growth in term neonatal pigs. Am J Physiol Endocrinol Metab 310: E699 -E713, 2016. First published February 16, 2016 doi:10.1152/ajpendo.00479.2015.-Neonatal pigs are used as a model to study and optimize the clinical treatment of infants who are unable to maintain oral feeding. Using this model, we have shown previously that pulsatile administration of leucine during continuous feeding over 24 h via orogastric tube enhanced protein synthesis in skeletal muscle compared with continuous feeding alone. To determine the long-term effects of leucine pulses, neonatal piglets (n ϭ 11-12/group) were continuously fed formula via orogastric tube for 21 days, with an additional parenteral infusion of either leucine (CON ϩ LEU; 800 mol·kg Ϫ1 ·h Ϫ1 ) or alanine (CON ϩ ALA) for 1 h every 4 h. The results show that body and muscle weights and lean gain were ϳ25% greater, and fat gain was 48% lower in CON ϩ LEU than CON ϩ ALA; weights of other tissues were unaffected by treatment. Fractional protein synthesis rates in longissimus dorsi, gastrocnemius, and soleus muscles were ϳ30% higher in CON ϩ LEU compared with CON ϩ ALA and were associated with decreased Deptor abundance and increased mTORC1, mTORC2, 4E-BP1, and S6K1 phosphorylation, SNAT2 abundance, and association of eIF4E with eIF4G and RagC with mTOR. There were no treatment effects on PKB, eIF2␣, eEF2, or PRAS40 phosphorylation, Rheb, SLC38A9, v-ATPase, LAMTOR1, LAMTOR2, RagA, RagC, and LAT1 abundance, the proportion of polysomes to nonpolysomes, or the proportion of mRNAs encoding rpS4 or rpS8 associated with polysomes. Our results demonstrate that pulsatile delivery of a leucine supplement during 21 days of continuous enteral feeding enhances lean growth by stimulating the mTORC1-dependent translation initiation pathway, leading to protein synthesis in skeletal muscle of neonates. leucine; growth; protein metabolism; orogastric feeding; infant GROWTH AND DEVELOPMENT DURING CHILDHOOD is the traditional measure of overall nutritional status. Poor growth in early infancy is associated with increased risk for adverse long-term health outcomes, including programming of obesity (63

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“…Some experimental models, predominantly in vitro, use labeled phenylalanine to estimate fractional protein synthesis, as leucine can stimulate its own corporation into protein. However, several studies show that even longterm or repeated dosing with leucine does not stimulate protein synthesis in porcine heart in vivo (2,10,53). Furthermore, preliminary studies in our laboratory showed no significant differences between estimated fractional protein synthesis values in porcine heart in vivo provided by infusion of 13 Clabeled phenylalanine and 13 C-labeled leucine.…”

Section: Discussionmentioning

confidence: 67%

Pyruvate modifies metabolic flux and nutrient sensing during extracorporeal membrane oxygenation in an immature swine model

Ledee¹,

Kajimoto²,

Priddy

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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-Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support for infants and children with postoperative cardiopulmonary failure. Nutritional support is mandatory during ECMO although specific actions for substrates on the heart have not been delineated. Prior work shows that enhancing pyruvate oxidation promotes successful weaning from ECMO. Accordingly, we tested the hypothesis that prolonged systemic pyruvate supplementation activates pyruvate oxidation in an immature swine model in vivo. Twelve male mixed-breed Yorkshire piglets (age 30 -49 days) received systemic infusion of either normal saline (group C) or pyruvate (group P) during the final 6 h of 8 h of ECMO. Over the final hour, piglets received [2-13 C] pyruvate, as a reference substrate for oxidation, and [13 C6]-L-leucine, as an indicator for amino acid oxidation and protein synthesis. A significant increase in lactate and pyruvate concentrations occurred, along with an increase in the absolute concentration of the citric acid cycle intermediates. An increase in anaplerotic flux through pyruvate carboxylation in group P occurred compared with no change in pyruvate oxidation. Additionally, pyruvate promoted an increase in the phosphorylation state of several nutrient-sensitive enzymes, like AMP-activated protein kinase and acetyl CoA carboxylase, suggesting activation for fatty acid oxidation. Pyruvate also promoted O-GlcNAcylation through the hexosamine biosynthetic pathway. In conclusion, although prolonged pyruvate supplementation did not alter pyruvate oxidation, it did elicit changes in nutrient-and energy-sensitive pathways. Therefore, the observed results support the further study of pyruvate and its downstream effect on cardiac function. extracorporeal membrane oxygenation; leucine; pyruvate; metabolism EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO) has been widely used in infants and children with life-threatening cardiopulmonary failure as both cardiac and respiratory support systems (16). Veno-arterial ECMO, especially, is frequently used as short-term extracorporeal life support for postoperative cardiopulmonary failure. However, unless adequate endogenous cardiac output and respiratory function ensue, patients are not able to be weaned from ECMO, and prolonged ECMO support can lead to higher morbidity and mortality (16,46). Thus ongoing research is attempting to identify nutritional supplements, which can improve recovery and prevent maladaptive cardiac remodeling. These potential supplements could enhance eventual weaning from mechanical circulation. Our prior work shows that successful adaptation and weaning after ECMO requires some metabolic flexibility (22). In particular, although ECMO independently promotes fatty acid oxidation (23), cardiac function after additional insult, such as ischemia reperfusion, can be improved by promoting oxidative flux through pyruvate dehydrogenase (11).Pyruvate serves as an important branch point of substrate metabolism (Fig. 1). However, the role of pyruvate as a metabolic substrat...

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

Cited by 50 publications

References 80 publications

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Conversion of leucine to β-hydroxy-β-methylbutyrate by α-keto isocaproate dioxygenase is required for a potent stimulation of protein synthesis in L6 rat myotubes

Pulsatile delivery of a leucine supplement during long-term continuous enteral feeding enhances lean growth in term neonatal pigs

Pyruvate modifies metabolic flux and nutrient sensing during extracorporeal membrane oxygenation in an immature swine model

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