Amino acid signaling in skeletal muscle is blunted by prematurity in a piglet model

Authors: RAMOS DOS SANTOS, ANTONIO - Texas A&M Agrilife; SURYAWAN, AGUS - Children'S Nutrition Research Center (CNRC); JANG, KI - Seoul National University; PARADA, ROSEMARIE - Texas A&M Agrilife; MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC); FIOROTTO, MARTA - Children'S Nutrition Research Center (CNRC); DAVIS, TERESA - Texas A&M Agrilife

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/1/2026
Publication Date: 2/1/2026
Citation: Ramos Dos Santos, A.C., Suryawan, A., Jang, K.B., Parada, R.D., Mohammad, M.A., Fiorotto, M.L., Davis, T.A. 2026. Amino acid signaling in skeletal muscle is blunted by prematurity in a piglet model. Journal of Nutrition. 156(2). Article 101303. https://doi.org/10.1016/j.tjnut.2025.101303.
DOI: https://doi.org/10.1016/j.tjnut.2025.101303

Interpretive Summary: Babies born prematurely often do not gain sufficient weight. Moreover, they tend to gain not enough muscle and too much fat. To understand why muscle growth is impaired in infants born preterm, we studied prematurely born pigs, as a model of preterm born human infants. The molecular mechanisms that are responsible for stimulating muscle protein synthesis after feeding were compared to those in piglets born full-term. The results showed that the molecules responsible for sensing an increase in amino acid availability after a meal are not as responsive in the muscle of preterm piglets as those in term-born piglets. As a result, protein synthesis will not be activated to the same extent and would reduce the muscle’s capacity to grow in premature babies.

Technical Abstract: Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.