Downregulated Translation Initiation Signaling Predisposes Low-Birth-Weight Neonatal Pigs to Slower Rates of Muscle Protein Synthesis

Abstract

Low-birth-weight (LBWT) neonates experience restricted muscle growth in their perinatal life. Our aim was to investigate the mechanisms that contribute to slower skeletal muscle growth of LBWT neonatal pigs. Twenty-four 1-day old male LBWT (816 ± 55 g) and normal-birth-weight (NBWT; 1,642 ± 55 g) littermates (n = 12) were euthanized to collect blood and longissimus dorsi (LD) muscle subsamples. Plasma glucose, insulin, and insulin-like growth factor-I (IGF-I) were lower in LBWT compared with NBWT pigs. Muscle IGF-I mRNA expression were lower in LBWT than NBWT pigs. However, IGF-I receptor mRNA and protein abundance was greater in LD of LBWT pigs. Abundance of myostatin and its receptors, and abundance and phosphorylation of smad3 were lower in LBWT LD by comparison with NBWT LD. Abundance of eukaryotic initiation factor (eIF) 4E binding protein 1 and mitogen-activated protein kinase-interacting kinases was lower in muscle of LBWT pigs compared with NBWT siblings, while eIF4E abundance and phosphorylation did not differ between the two groups. Furthermore, phosphorylation of ribosomal protein S6 kinase 1 (S6K1) was less in LBWT muscle, possibly due to lower eIF3e abundance. In addition, abundance and phosphorylation of eIF4G was reduced in LBWT pigs by comparison with NBWT littermates, suggesting translation initiation complex formation is compromised in muscle of LBWT pigs. In conclusion, diminished S6K1 activation and translation initiation signaling are likely the major contributors to impaired muscle growth in LBWT neonatal pigs. The upregulated IGF-I R expression and downregulated myostatin signaling seem to be compensatory responses for the reduction in protein synthesis signaling.

Decreased abundance of eIF4F subunits predisposes low birth weight neonatal pigs to reduced muscle hypertrophy

“…Our data also indicated that phosphorylation of the downstream effector of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), is weaker in LBWT muscle lysates than NBWT controls (9). In addition, mitogen-activated protein kinase-interacting kinases (MNKs), which regulate translation initiation by phosphorylating eukaryotic translation initiation factor (eIF)4E at Ser 209 , were less abundant in LBWT muscle lysates (9). These data would suggest that reduced muscle growth in LBWT pigs reflects impaired translation initiation and thus protein synthesis, but it is unclear if this coincides with the activation of protein degradation pathways.…”

“…Thus, satellite cells are not intrinsically different between the two groups and are unlikely a major contributor to the impaired muscle growth of LBWT pigs (10). Our data also indicated that phosphorylation of the downstream effector of mammalian target of rapamycin (mTOR), ribosomal protein S6 kinase 1 (S6K1), is weaker in LBWT muscle lysates than NBWT controls (9). In addition, mitogen-activated protein kinase-interacting kinases (MNKs), which regulate translation initiation by phosphorylating eukaryotic translation initiation factor (eIF)4E at Ser 209 , were less abundant in LBWT muscle lysates (9).…”

“…Pregnant sows (Landrace ϫ Hampshire) had free access to water and were fed daily a corn-soybean meal diet to meet US National Research Council (2012) requirements for gestating sows. Piglets were weighed at birth and defined as NBWT when weight was within Ϯ0.5 SD or LBWT when weight was Յ2 SD of the litter average (9,10). Male (n ϭ 8 pairs) and female (n ϭ 8 pairs) one-day-old NBWT (1,705 Ϯ 41 g) and LBWT (925 Ϯ 41 g) pigs (n ϭ 16) were used.…”

“…Real-time PCR. Analysis of gene expression was performed as described previously (9). Briefly, skeletal muscle total RNA was extracted and purified using the Direct-zol RNA Miniprep Kit (ZYMO Research, Orange, CA).…”

Impacto del peso al nacimiento del lechón sobre los balances de nitrógeno y energía en la fase de crecimiento

“…Una menor concentración sérica de serotonina y triptófano (33) . Además, los lechones PBN tienen una menor tasa de síntesis de proteína (34) y una mayor tasa de degradación de proteína (35) ; no se sabe si estas características están presentes o desaparecen durante su crecimiento post destete; y aunado esto a que este tipo de animales tienen un menor número de células musculares (2,(36)(37)(38) . Por lo que es muy probable que todos los factores mencionados afecten el uso metabólico de los nutrientes, ya que la capacidad de deposición de tejido magro (proteína) es reducida.…”