Impact of Prematurity on Nutrient Signaling and Protein Synthesis in Skeletal Muscle

Preterm birth disrupts nutrient-responsive signaling pathways critical for skeletal muscle growth and long-term metabolic health. Despite improvements in neonatal care, preterm infants often experience postnatal growth failure marked by impaired lean mass accretion. This review examines how prematurity intrinsically alters insulin and amino acid signaling to mechanistic target of rapamycin complex 1 (mTORC1), a central regulator of translation initiation and protein synthesis. Evidence from translational models reveals blunted activation of mTORC1 and its downstream effectors, independent of birth weight or comorbidities. Defects in insulin-PDK1/mTORC2-Akt signaling and amino acid sensing, particularly leucine sensing, contribute to impaired mTORC1-dependent translation initiation and reduced muscle protein synthesis. Feeding strategies that mimic physiological nutrient pulsatility, including intermittent bolus feeding and pulsatile leucine supplementation during continuous feeding, show promise in restoring anabolic signaling. Understanding these molecular impairments provides a foundation for targeted nutritional and therapeutic interventions to improve muscle growth and mitigate long-term health risks in individuals born preterm.