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Session: Nutrient Signaling by Amino Acids and Energy (Oral 20)

(OR20-02-23) Skeletal Muscle Protein Synthesis Is Enhanced by Leucine Supplementation in a Preterm Piglet Model Through a Sestrin2•GATOR2 and RagA•mTORC1 Signaling Pathway

Monday, July 24, 2023
2:12 PM – 2:24 PM ET
Location:  Back Bay A

    Presenting Author(s)

  • AS

    Agus Suryawan, PhD

    Instructor
    Children's Nutrition Research Center, Baylor College of Medicine
    Houston, Texas, United States

    Disclosure information not submitted.

    • Co-Author(s)

  • Erin A. Posey, PhD (she/her/hers)

    Developmental Biologist
    USDA/APHIS - National Veterinary Services Lab
    Ames, Iowa, United States

    • Co-Author(s)

  • HN

    Hanh Nguyen, B.Sc.

    Children's Nutrition Research Center, Baylor College of Medicine
    Houston, Texas, United States

  • Christina M. Sciarrillo, PhD, RD

    Postdoctoral Fellow
    National Institute of Diabetes and Digestive and Kidney Disease
    Rockville, Maryland, United States

  • BS

    Barbara Stoll, PhD

    Children's Nutrition Research Center, Baylor College of Medicine
    Houston, Texas, United States

  • CV

    Caitlin Vonderohe, DVM, PhD

    Children's Nutrition Research Center, Baylor College of Medicine

  • DB

    Doug G. Burrin, PhD

    Children's Nutrition Research Center, Baylor College of Medicine
    Houston, Texas, United States

  • Marta L. Fiorotto, Ph.D.

    Children's Nutrition Research Center, Baylor College of Medicine
    Houston, Texas, United States

  • Teresa A. Davis, PhD (she/her/hers)

    Professor, Pediatrics-Nutrition
    Children's Nutrition Research Center, Baylor College of Medicine
    Houston, Texas, United States

Disclosure(s):
Erin A. Posey, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Agus Suryawan, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Christina M. Sciarrillo, PhD, RD: No relevant financial relationship(s) with ineligible companies to disclose.
Teresa A. Davis, PhD: No relevant financial relationship(s) with ineligible companies to disclose.
Objectives: Extrauterine growth restriction is common in preterm infants and is associated with reduced lean growth and long-term morbidities. Previous work in our lab showed that leucine acts as a nutrient signal to stimulate protein synthesis, and that in neonatal pigs born at term intermittent parenteral leucine (Leu) pulses during continuous feeding increases skeletal muscle mTORC1 signaling and protein synthesis. We hypothesized that leucine pulsing during continuous feeding enhances mTORC1 signaling via a Sestrin-mediated pathway to increase protein synthesis in a preterm piglet model.

Methods: Pigs delivered by cesarean section at 105 d gestation were gradually transitioned over 7 d from parenteral to enteral feeding, via an orogastric tube, and continuously fed a protein and energy balanced milk-replacer diet (ME = 195 kcal/kg/d; Protein = 13.5 g/kg/d) for the remainder of the study (17 d). Pigs were randomly assigned to either: 1) Leu (LEU; 1.6 mmol/kg bodyweight/4 h; n = 12) or Alanine (ALA; 1.6 mmol Ala/kg bodyweight/4 h; isonitrogenous control; n = 11) groups. The assigned amino acid solutions were administered i.v. as a “pulse” 1 h, every 4 h from day 3 to 24 of study. Indices of amino acid signaling and mTORC1 activation were determined postprandially, 60 min after initiation of the last pulse on day 24.

Results: Final body weight was higher (P < 0.05) and longissimus dorsi muscle weight was heavier in LEU than ALA pigs (P = 0.01). Upstream of mTORC1 activation, the abundance of the Sestrin2-GATOR2 complex was lower and the RagA-mTORC1 complex was higher in longissimus dorsi (LD) and gastrocnemius muscle of LEU compared to ALA pigs (P < 0.05). Downstream of mTORC1, the phosphorylation of S6K1 and 4EBP1 and abundance of the eIF4E-eIF4G complex were higher in LD and gastrocnemius muscle of LEU compared to ALA pigs (P < 0.05). Fractional rates of protein synthesis in LD and gastrocnemius muscle were higher in LEU compared to ALA pigs (P < 0.05).

Conclusions: These results show that leucine supplementation enhances mTORC1-activated translation initiation in skeletal muscle of the preterm piglet via a leucine-sensing pathway mediated by Sestrin2 and the Rag proteins. This leucine-mediated cascade promotes skeletal muscle and body weight gain by increasing muscle protein synthesis.

Funding Sources: NIH-NICHD