191 Pulsatile Administration of Leucine Promotes mTOR Signaling and Protein Synthesis in Skeletal Muscle of Continuously Fed Preterm Pigs

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 102-102
Author(s):  
Marko Rudar ◽  
Agus Suryawan ◽  
Hanh Nguyen ◽  
Barbara Stoll ◽  
Douglas Burrin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Mtor Signaling ◽  
Oral Feeding ◽  
Anabolic Response ◽  
Intermittent Feeding ◽  
Longissimus Dorsi Muscle ◽  
Pulsatile Administration ◽  
Continuous Feeding ◽  
L1 And L2

Abstract Continuous feeding does not elicit an optimal anabolic response but is required for some premature infants. We reported previously that intermittent intravenous pulses of Leu (800 μmol Leu·kg-1·h-1 every 4 h) to continuously fed pigs born at term enhanced skeletal muscle mTOR signaling and protein synthesis (PS). The objective of this study was to determine if the anabolic response of skeletal muscle to intermittent Leu pulses is altered following premature birth. Pigs delivered 10 d preterm by cesarean section were advanced to full oral feeding over four days (195 kcal·kg-1·d-1; 13.5 g protein·kg-1·d-1). Pigs were assigned to 1 of 4 treatments: 1) ALA (continuous feeding; 800 μmol Ala·kg-1·h-1 every 4 h; n = 7); 2) L1× (continuous feeding; 800 μmol Leu·kg-1·h-1 every 4 h; n = 6); 3) L2× (continuous feeding; 1600 μmol Leu·kg-1·h-1 every 4 h; n = 6); and 4) INT (intermittent feeding every 4 h; n = 5). Pigs received a Phe tracer 30 min following the amino acid pulse or intermittent feeding to measure PS in longissimus dorsi muscle. Anabolic signaling downstream of mTOR was determined by immunoblot.ResultsPS was higher in L2× and INT compared to ALA (P < 0.05) but was not different between L2× and INT; PS in L1× was intermediate and not different from other groups. Phosphorylation of 4EBP1 and S6K1 was higher in INT compared to L1× and ALA groups (P < 0.05) but was not different compared to L2×. Phosphorylation of 4EBP1, but not S6K1, was higher in L2× compared to ALA (P < 0.05); phosphorylation of 4EBP1 and S6K1 was not different between L1× and L2×.ConclusionsThese results demonstrate that intravenous Leu enhances mTOR activation and PS in LD muscle of continuously fed preterm pigs. However, the amount required may be higher than in pigs born at term.Source of Research SupportNIH and USDA.

scholarly journals Intermittent Leucine Pulses Enhance Skeletal Muscle mTOR Signaling and Protein Synthesis in Continuously Fed Preterm Pigs

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 543-543
Author(s):  
Marko Rudar ◽  
Agus Suryawan ◽  
Hanh Nguyen ◽  
Barbara Stoll ◽  
Douglas Burrin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Feeding Tube ◽  
Mtor Signaling ◽  
Skeletal Muscle Protein ◽  
Intermittent Feeding ◽  
Longissimus Dorsi Muscle ◽  
Continuous Feeding

Abstract Objectives Extrauterine growth restriction in premature infants is associated with reduced lean mass and long-term morbidities. We have reported previously that intermittent parenteral pulses of Leu promote skeletal muscle mTOR signaling and protein synthesis of continuously fed neonatal pigs born at term. The objective of this study was to determine the effect of prematurity on the response of skeletal muscle anabolic pathways to intermittent parenteral Leu pulses in continuously fed pigs. Methods Pigs delivered 10 d preterm by C-section were fitted with jugular vein and carotid artery catheters and an orogastric feeding tube. Pigs were advanced from parenteral to enteral feeding over 4 d (195 kcal · kg−1 · d−1; 13.5 g protein · kg−1 · d−1). On day 4, pigs were assigned to 1 of 4 treatments: 1) ALA (continuous feeding, 7.5 mL · kg−1 · h−1; 800 μmol Ala · kg−1 · h−1 every 4 h; n = 7); 2) L1 × (continuous feeding; 800 μmol Leu · kg−1 · h−1 every 4 h; n = 6); 3) L2 × (continuous feeding; 1600 μmol Leu · kg−1 · h−1 every 4 h; n = 6); and 4) INT (intermittent feeding; 30 mL · kg−1 fed over 15 min every 4 h; n = 5). On day 5, pigs received L-[ring-2H5]-Phe 30 min after starting the pulse (groups 1, 2, and 3) or meal feeding (group 4). Pigs were euthanized 30 min after isotope injection and longissimus dorsi muscle was collected. Protein synthesis was determined by LC/MS-MS. Indices of amino acid signaling and mTOR activation were determined by immunoprecipitation and immunoblot assays. Results Skeletal muscle protein synthesis was higher in L2 × (+37%) and INT (+31%) compared to ALA (P < 0.05), but was not different between L2 × and INT; protein synthesis in L1 × was intermediate and not different from all other groups. The phosphorylation of 4EBP1, downstream of mTOR, was higher in L2 × and INT compared to ALA (P < 0.05), whereas 4EBP1 phosphorylation in L1 × was lower compared to INT (P < 0.05) but not different compared to ALA and L2 × . The abundance of mTOR · RagA complex, upstream of mTOR and activated in response to Leu, was higher in L2 × and INT compared to ALA and L1 × (P < 0.05). Conclusions These results show that parenteral Leu can enhance anabolic signaling and protein synthesis in skeletal muscle during continuous feeding in preterm pigs, but the dose required is higher than in pigs born at term. Funding Sources Research was supported by NIH and USDA.

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

2016 ◽  
Vol 310 (8) ◽  
pp. E699-E713 ◽  
Author(s):  
Claire Boutry ◽  
Samer W. El-Kadi ◽  
Agus Suryawan ◽  
Julia Steinhoff-Wagner ◽  
Barbara Stoll ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Enteral Feeding ◽  
Oral Feeding ◽  
Orogastric Tube ◽  
Neonatal Pigs ◽  
Lean Growth ◽  
Continuous Feeding ◽  
Pulsatile Delivery

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 = 11–12/group) were continuously fed formula via orogastric tube for 21 days, with an additional parenteral infusion of either leucine (CON + LEU; 800 μmol·kg−1·h−1) or alanine (CON + ALA) for 1 h every 4 h. The results show that body and muscle weights and lean gain were ∼25% greater, and fat gain was 48% lower in CON + LEU than CON + ALA; weights of other tissues were unaffected by treatment. Fractional protein synthesis rates in longissimus dorsi, gastrocnemius, and soleus muscles were ∼30% higher in CON + LEU compared with CON + 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, eIF2α, 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.

scholarly journals Differential Regulation of Protein Synthesis and mTOR Signaling in Skeletal Muscle and Visceral Tissues of Neonatal Pigs after a Meal

2010 ◽  
Vol 24 (S1) ◽  
Author(s):  
Maria C Gazzaneo ◽  
Agus Suryawan ◽  
Renán A. Orellana ◽  
Roberto Murgas Torrazza ◽  
Hanh V. Nguyen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Differential Regulation ◽  
Mtor Signaling ◽  
Neonatal Pigs

scholarly journals Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation

2018 ◽  
Vol 314 (5) ◽  
pp. R741-R751 ◽  
Author(s):  
Nobuki Moriya ◽  
Mitsunori Miyazaki
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Protein Synthesis ◽  
Satellite Cell ◽  
Muscle Mass ◽  
Satellite Cells ◽  
Muscle Hypertrophy ◽  
Mtor Signaling ◽  
Skeletal Muscle Hypertrophy ◽  
Satellite Cell Proliferation

Skeletal muscle mass is determined by the net dynamic balance between protein synthesis and degradation. Although the Akt/mechanistic target of rapamycin (mTOR)-dependent pathway plays an important role in promoting protein synthesis and subsequent skeletal muscle hypertrophy, the precise molecular regulation of mTOR activity by the upstream protein kinase Akt is largely unknown. In addition, the activation of satellite cells has been indicated as a key regulator of muscle mass. However, the requirement of satellite cells for load-induced skeletal muscle hypertrophy is still under intense debate. In this study, female germline Akt1 knockout (KO) mice were used to examine whether Akt1 deficiency attenuates load-induced skeletal muscle hypertrophy through suppressing mTOR-dependent signaling and satellite cell proliferation. Akt1 KO mice showed a blunted hypertrophic response of skeletal muscle, with a diminished rate of satellite cell proliferation following mechanical overload. In contrast, Akt1 deficiency did not affect the load-induced activation of mTOR signaling and the subsequent enhanced rate of protein synthesis in skeletal muscle. These observations suggest that the load-induced activation of mTOR signaling occurs independently of Akt1 regulation and that Akt1 plays a critical role in regulating satellite cell proliferation during load-induced muscle hypertrophy.

Acute effects of lactic acid-fermented and enzyme-digested soybean on protein synthesis via mTOR signaling in the skeletal muscle

2020 ◽  
Vol 84 (11) ◽  
pp. 2360-2366
Author(s):  
Kohei Ono ◽  
Minoru Tanaka ◽  
Takuya Ikeji ◽  
Ryosuke Nakanishi ◽  
Takumi Hirabayashi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Lactic Acid ◽  
Mtor Signaling ◽  
Acute Effects

Leucine-stimulated mTOR signaling is partly attenuated in skeletal muscle of chronically uremic rats

2011 ◽  
Vol 301 (5) ◽  
pp. E873-E881 ◽  
Author(s):  
Yu Chen ◽  
Sumita Sood ◽  
Kevin McIntire ◽  
Richard Roth ◽  
Ralph Rabkin
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Signaling Pathway ◽  
Muscle Wasting ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mtor Signaling ◽  
Mtor Signaling Pathway ◽  
Exercise Induced ◽  
Rps6 Phosphorylation

The branched-chain amino acid leucine stimulates muscle protein synthesis in part by directly activating the mTOR signaling pathway. Furthermore, leucine, if given in conjunction with resistance exercise, enhances the exercise-induced mTOR signaling and protein synthesis. Here we tested whether leucine can activate the mTOR anabolic signaling pathway in uremia and whether it can enhance work overload (WO)-induced signaling through this pathway. Chronic kidney disease (CKD) and control rats were studied after 7 days of surgically induced unilateral plantaris muscle WO and a single leucine or saline load. In the basal state, 4E-BP1 phosphorylation was modestly depressed in non-WO muscle of CKD rats, whereas rpS6 phosphorylation was nearly completely suppressed. After oral leucine mTOR, S6K1 and rpS6 phosphorylation increased similarly in both groups, whereas the phospho-4E-BP1 response was modestly attenuated in CKD. WO alone activated the mTOR signaling pathway in control and CKD rats. In WO CKD, muscle leucine augmented mTOR and 4E-BP1 phosphorylation, but its effect on S6K1 phosphorylation was attenuated. Taken together, this study has established that the chronic uremic state impairs basal signaling through the mTOR anabolic pathway, an abnormality that may contribute to muscle wasting. However, despite this abnormality, leucine can stimulate this signaling pathway in CKD, although its effectiveness is partially attenuated, including in skeletal muscle undergoing sustained WO. Thus, although there is some resistance to leucine in CKD, the data suggest a potential role for leucine-rich supplements in the management of uremic muscle wasting.

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

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

scholarly journals Intermittent Bolus Feeding Enhances Organ Growth More Than Continuous Feeding in a Neonatal Piglet Model

2020 ◽  
Vol 4 (12) ◽  
Author(s):  
Samer W El-Kadi ◽  
Claire Boutry-Regard ◽  
Agus Suryawan ◽  
Hanh V Nguyen ◽  
Scot R Kimball ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Weight Gain ◽  
Translation Initiation ◽  
Initiation Factor ◽  
Whole Body ◽  
Feeding Frequency ◽  
Organ Growth ◽  
Intermittent Feeding ◽  
Intermittent Bolus ◽  
Continuous Feeding

ABSTRACT Background Orogastric tube feeding is frequently prescribed for neonates who cannot ingest food normally. In a piglet model of the neonate, greater skeletal muscle growth is sustained by upregulation of translation initiation signaling when nutrition is delivered by intermittent bolus meals, rather than continuously. Objectives The objective of this study was to determine the long-term effects of feeding frequency on organ growth and the mechanism by which feeding frequency modulates protein anabolism in these organs. Methods Eighteen neonatal pigs were fed by gastrostomy tube the same amount of a sow milk replacer either by continuous infusion (CON) or on an intermittent bolus schedule (INT). After 21 d of feeding, the pigs were killed without interruption of feeding (CON; n = 6) or immediately before (INT-0; n = 6) or 60 min after (INT-60; n = 6) a meal, and fractional protein synthesis rates and activation indexes of signaling pathways that regulate translation initiation were measured in the heart, jejunum, ileum, kidneys, and liver. Results Compared with continuous feeding, intermittent feeding stimulated the growth of the liver (+64%), jejunum (+48%), ileum (+40%), heart (+64%), and kidney (+56%). The increases in heart, kidney, jejunum, and ileum masses were proportional to whole body lean weight gain, but liver weight gain was greater in the INT-60 than the CON, and intermediate for the INT-0 group. For the liver and ileum, but not the heart, kidney, and jejunum, INT-60 compared with CON pigs had greater fractional protein synthesis rates (22% and 48%, respectively) and was accompanied by an increase in ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E binding protein 1 phosphorylation. Conclusions These results suggest that intermittent bolus compared with continuous orogastric feeding enhances organ growth and that in the ileum and liver, intermittent feeding enhances protein synthesis by stimulating translation initiation.

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

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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