Prematurity blunts the insulin- and amino acid-induced stimulation of translation initiation and protein synthesis in skeletal muscle of neonatal pigs

Abstract

Extrauterine growth restriction in premature infants is largely attributed to reduced lean mass accretion and is associated with long-term morbidities. Previously, we demonstrated that prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in skeletal muscle of neonatal pigs. The objective of the current study was to determine whether the blunted feeding response is mediated by reduced responsiveness to insulin, amino acids, or both. Pigs delivered by Cesarean section preterm (PT; 103 d, n = 25) or at term (T; 112 d, n = 26) were subject to euinsulinemic-euaminoacidemic-euglycemic (FAST), hyperinsulinemic-euaminoacidemic-euglycemic (INS), or euinsulinemic-hyperaminoacidemic-euglycemic (AA) clamps 4 d after delivery. Indices of mechanistic target of rapamycin complex 1 (mTORC1) signaling and fractional protein synthesis rates were measured after 2 h. While longissimus dorsi (LD) muscle protein synthesis increased in response to both INS and AA, the increase was 28% lower in PT than T. Upstream of mTORC1, Akt phosphorylation, an index of insulin signaling, was increased with INS but was 40% less in PT than T. The abundances of mTOR·RagA and mTOR·RagC, indices of amino acid signaling, increased with AA but were 25% less in PT than T. Downstream of mTORC1, eIF4E·eIF4G abundance was increased by both INS and AA but attenuated by prematurity. These results suggest that preterm birth blunts both insulin- and amino acid-induced activation of mTORC1 and protein synthesis in skeletal muscle, thereby limiting the anabolic response to feeding. This anabolic resistance likely contributes to the high prevalence of extrauterine growth restriction in prematurity.

Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies

“…Insulin-stimulated glucose uptake is crucial for muscle contraction. Insulin is a powerful synthetic signal that significantly stimulates muscle protein synthesis ( 39 ). Classical insulin signaling pathways and anabolic stimuli, including PI3K, 3-phosphoinositide-dependent kinase 1 (PDK1), AKT, mTOR, and p70S6K, activate protein synthesis and thereby promote muscle growth ( 40 , 41 ).…”

Intermittent bolus feeding does not enhance protein synthesis, myonuclear accretion, or lean growth more than continuous feeding in a premature piglet model

“…In this study, we investigated how intermittent bolus and continuous feeding modalities impact muscle anabolic signaling and protein synthesis, SC abundance, myonuclear accretion, and body composition in a preterm neonatal pig model of the premature infant ( 27 ). A key motivation for this study was the observation that, although feeding, insulin, and amino acids all promote anabolic signaling and protein synthesis in skeletal muscle in pigs born preterm and at term, the magnitude of the response is blunted in preterm compared with term pigs ( 25 , 26 ); if persistent, this could mitigate any advantage of intermittent feeding following premature birth.…”

“…Compared with full-term pigs, prematurity produced a marked reduction in LD muscle insulin and amino acid signaling to mTORC1 after feeding. More recently, we showed that mTORC1 signaling and protein synthesis in skeletal muscle are blunted in response to equivalent and sustained increases in both insulin and amino acids in preterm compared with term pigs during hyperinsulinemic and hyperaminoacidemic clamps ( 26 ). This blunted insulin- and amino acid-induced mTORC1 activation was associated with reduced Akt phosphorylation and mTOR·Rag association, respectively, in muscle of preterm compared with term pigs.…”

“…Recently, our research group demonstrated that the activation of insulin and amino acid signaling upstream of mTORC1, translation initiation factor signaling downstream of mTORC1, and protein synthesis in skeletal muscle in response to feeding are diminished in preterm compared with full-term neonatal pigs, and this blunted response contributes to reduced weight gain ( 25 ). Moreover, our recent hyperinsulinemic-euaminoacidemic-euglycemic and euinsulinemic-hyperaminoacidemic-euglycemic clamp studies demonstrated that mTORC1 signaling and protein synthesis in skeletal muscle of preterm pigs are blunted in response to equivalent increases in both insulin and amino acids ( 26 ). Considering this blunted anabolic response to feeding, it is unclear whether pigs born preterm can respond to intermittent bolus and continuous feeding modalities in the same manner as pigs born at term.…”

Organ Growth and Intestinal Functions of Preterm Pigs Fed Low and High Protein Formulas With or Without Supplemental Leucine or Hydroxymethylbutyrate as Growth Promoters

“…Leucine elicited an even greater growth response to the lower protein milk replacer but did not increase growth when added to the high protein formula that provided 12 g protein per kg-day. Protein synthesis of preterm pigs provided 16 g per kg-d of amino acids is lower compared with term pigs (22). Similar to human infants, fetal and postnatal growth rates are related for pigs (23) and small term pigs grow slower than normal birth weight littermates (24).…”