# Amino Acid Signaling in Skeletal Muscle Is Blunted by Prematurity in a Piglet Model

## TL;DR

Premature birth in piglets disrupts amino acid signaling in skeletal muscle, leading to reduced protein synthesis and growth.

## Contribution

This study identifies specific amino acid-sensing pathways impaired by prematurity, linking them to anabolic resistance in skeletal muscle.

## Key findings

- Prematurity blunts AA-induced dissociation of Sestrin1-GATOR2 complexes in piglet skeletal muscle.
- Sensor abundances for leucine, threonine, and branched-chain amino acids are reduced in preterm piglets.
- Amino acid-induced mTORC1 activation is impaired in preterm piglets compared to term.

## Abstract

Preterm (PT) infants are at increased risk for reduced postnatal lean mass accretion. We established that the feeding-induced stimulation of protein synthesis in skeletal muscle is blunted in piglets born PT compared with those born at term.

We evaluated the extent to which key components of the amino acid–sensing pathways that regulate mechanistic target of rapamycin complex 1 (mTORC1) activation contribute to anabolic resistance in skeletal muscle of piglets born PT compared with those born term.

Piglets delivered by cesarean section 10 d PT (n = 23) or at term (n = 22) were administered total parenteral nutrition for 3 d. On day 4, euinsulinemic-euaminoacidemic-euglycemic (FAST group), hyperinsulinemic-euaminoacidemic-euglycemic (INS group), or euinsulinemic-hyperaminoacidemic-euglycemic (AA group) clamps were performed for 2 h. Abundances and activation of amino acid signaling components in skeletal muscle were analyzed by immunoblotting.

Abundances of amino acid transporters LAT1/SLC7A5 (leucine), SLC38A9 (arginine), and SNAT2/SLC38A2 (glutamine) were unaffected by prematurity. Sestrin1- and Sestrin2-GATOR2 abundances were reduced (P < 0.05) by AA, consistent with leucine-induced dissociation of these inhibitory complexes; prematurity blunted this effect for Sestrin1-GATOR2 (P < 0.05). SAR1B, but not LARS-mTOR, leucine-sensor abundances were lower in PT than term animals (P < 0.05). TARS2 (threonine) and RAB1A (branched-chain amino acid) sensor abundances were lower in PT (P < 0.05). Arginine (CASTOR1-GATOR2), methionine (SAMTOR-GATOR1), and glutamine (ARF1) sensor abundances were unaffected by prematurity. AA-induced formations of RagA- and RagC-mTOR complexes were attenuated in PT compared with term piglets (P < 0.05). Both AA and INS stimulated mTORC1 phosphorylation, but these effects were blunted by prematurity.

PT birth impairs the abundance and activation of multiple amino acid–sensing components upstream of mTORC1 in skeletal muscle. This disruption attenuates amino acid–induced mTORC1-dependent translation initiation and protein synthesis and likely contributes to the anabolic resistance, reduced lean mass, and extrauterine growth faltering frequently observed in premature infants.