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

Abstract

Muscle hypertrophy is limited in low birth weight (LBWT) neonates, suggesting a reduction in protein synthesis and increased protein degradation. Sixteen pairs of one-day-old normal birth weight (NBWT) and LBWT littermates ( n = 16) were euthanized, and the longissimus dorsi (LD) was sampled for protein abundance and kinase phosphorylation profile measures. Eukaryotic initiation factor (eIF)4E and eIF4G abundance, and assembly of the active eIF4E-eIF4G complex, was less for LBWT than for NBWT pig muscles. Similarly, eIF3f abundance was reduced in the muscle of LBWT compared with NBWT pigs and was associated with diminished ribosomal protein S6 kinase 1 phosphorylation. This decrease was linked to a lower phosphorylation of programmed cell death protein 4 (PDCD4) in LBWT pig muscle. By contrast, PDCD4 abundance was greater in the muscle of the LBWT than NBWT group, suggesting lower release and availability of eIF4A from the PDCD4-eIF4A complex. Moreover, protein abundance of eIF4A was lower in LBWT muscle, which is expected to further impair the formation of eIF4F translation initiation complex. Microtubule-associated light chain 3 (LC3) II to total LC3 ratio was greater in LBWT LD lysates, yet P62 abundance was similar between the two groups, suggesting no difference in autophagy. Muscle atrophy F-box (atrogin-1) abundance was less in LBWT LD lysates, suggesting decreased degradation through the ubiquitin-proteasome system. In conclusion, limited eIF4F subunit abundance and downregulated translation initiation are plausible mechanisms for diminished muscle growth in LBWT compared with NBWT neonatal pigs. NEW & NOTEWORTHY We demonstrated that eukaryotic initiation factor (eIF)4E, eIF4G, and eIF4A abundance, and assembly of the active eIF4E-eIF4G complex, were reduced in low birth weight (LBWT) compared with normal birth weight pig muscle. In contrast, our data indicated that protein degradation signaling does not seem to affect protein turnover in LBWT pig muscle. Thus, downregulated translation initiation is likely the key contributor that predisposes LBWT neonatal pigs to slower postnatal muscle growth.