(OR20-01-23) Preterm Birth Blunts Amino Acid Sensing and Signaling Components Toward mTORC1 Activation in Skeletal Muscle of a Piglet Model

Objectives: Infants born preterm are at increased risk for being underweight and stunted in early life. Previously, we showed in a neonatal piglet model that the feeding-induced stimulation of skeletal muscle protein synthesis is reduced by preterm birth. This anabolic resistance was linked to reduced mTORC1 activation in response to both insulin (INS) and amino acids (AA). To determine underlying mechanisms, we assessed key regulatory AA sensing components involved in AA-induced activation of mTORC1 in skeletal muscle of preterm compared to term piglets.

Methods: Piglets were delivered by cesarean section 10 d (preterm/PT; n=25, equivalent to human infant at 30 wk gestation) or 2 d (term/T; n =26) before term birth. Total parenteral nutrition was administered for 3 days and on day 4, euinsulinemic-euaminoacidemic-euglycemic (FAST), hyperinsulinemic-euaminoacidemic-euglycemic (INS), or euinsulinemic-hyperaminoacidemic-euglycemic (AA) clamps were performed. Longissimus dorsi muscle was collected after 2 h. The abundance and activation of AA signaling components were analyzed by immunoblotting.

Results: The protein abundances of the AA transporters for glutamine (SLC38A2), leucine (SLC7A5), and arginine (SLC38A9) did not differ between PT and T. The abundance of the leucine sensor SAR1B (P < 0.05), but not Sestrin 2 and LRS, was lower in PT than in T. The abundances of the threonine sensor, TARS2 (P < 0.05) and the AA sensor, RAB1A (P < 0.05), but not the glutamine sensor, ARF1, were lower in PT than T. There was no effect of acute AA or INS on SNAT2, LAT1, SLC38A9, SAR1B, Sestrin 2, LRS, TARS2, RAB1A, and ARF1 protein abundances. The abundance of the mTOR-RagA and mTOR-RagC complexes were enhanced with AA, but not INS, compared to FAST pigs and were lower in PT than in T pigs. The phosphorylation of mTORC1, and thus, its activation, was induced by both AA and INS but these responses were lower in PT than T (P < 0.05).

Conclusions: These results suggest that preterm birth attenuates the activation and abundance of some of the AA sensing components that play pivotal roles in mTORC1 activation towards translation initiation and protein synthesis in skeletal muscle. This reduced anabolic response to amino acids likely contributes to the reduced lean mass and extrauterine growth restriction of premature infants.

Funding Sources: Source of Research Support: NIH and USDA