Prematurity Negatively Alters Activation of the Amino Acid Signaling Pathway That Regulates Protein Synthesis in Muscle of a Preterm Piglet Model

OBJECTIVES: Preterm birth is often associated with reduced postnatal lean mass gain. Recently we found that postnatal weight gain and postprandial skeletal muscle protein synthesis in prematurely born piglets were blunted compared to term born pigs. This anabolic resistance is associated with reduced activation of mTORC1, a central regulator of protein synthesis. To identify the responsible mechanisms, we evaluated key regulatory components involved in the amino acid (AA)-induced activation of mTORC1 in skeletal muscle in preterm compared to term pigs. METHODS: Piglets were delivered by cesarean section 11 d (preterm/PT, equivalent to 28–32 wk gestation in humans) or 2 d (term/T) before term; a jugular vein catheter was placed for delivery of total parenteral nutrition. On day 3, after 4 h fasting, piglets were fasted one additional h or fed an elemental diet (31.5 kcal/kg, 1.3 g/kg lactose, 2.7 g/kg AA, and 1.6 g/kg lipid), via oral gavage. Longissimus dorsi muscle was collected following euthanasia (fasted state or 60 min after feeding). The abundance and activation of AA signaling components were determined by immunoprecipitation and immunoblotting assays. RESULTS: The abundances of AA transporters SNAT2/SLC38A2 (glutamine), LAT1/SLC7A5 (leucine), PAT1/SLC36A1 (H+AA), and SLC38A9 (arginine) were not affected by prematurity. Lysosomal-associated protein abundances (GATOR2, LAMTOR1/2, V-ATPase, Rag A/C, and Rheb) were similar in PT and T. Although the abundance of leucine sensors (Sestrin 2 and LRS) and the Sestrin2-GATOR2 complex were similar, the association of mTOR with RagA and RagC were lower post-feeding in PT than in T pigs (P < 0.05). Consequently, the activation of mTORC1, indicated by phosphorylation of Ser(2448), was lower in PT than in T pigs after a meal (P < 0.05). CONCLUSIONS: These results showed that the postprandial AA-induced activation of mTORC1 is reduced following preterm birth. Although AA transporter abundance is not altered by prematurity, the postprandial activation of the Rag signaling components that regulate mTORC1 activation is impaired by prematurity. The reduced AA-induced activation of mTORC1 likely contributes to the extrauterine growth faltering of prematurity. FUNDING SOURCES: NIH and USDA.