Phosphorylation of eukaryotic initiation factor 4E is dispensable for skeletal muscle hypertrophy

Am J Physiol Cell Physiol. 2019 Dec 1;317(6):C1247-C1255. doi: 10.1152/ajpcell.00380.2019. Epub 2019 Oct 9.

Abstract

The eukaryotic initiation factor 4E (eIF4E) is a major mRNA cap-binding protein that has a central role in translation initiation. Ser209 is the single phosphorylation site within eIF4E and modulates its activity in response to MAPK pathway activation. It has been reported that phosphorylation of eIF4E at Ser209 promotes translation of key mRNAs, such as cyclin D1, that regulate ribosome biogenesis. We hypothesized that phosphorylation at Ser209 is required for skeletal muscle growth in response to a hypertrophic stimulus by promoting ribosome biogenesis. To test this hypothesis, wild-type (WT) and eIF4E knocked-in (KI) mice were subjected to synergist ablation to induce muscle hypertrophy of the plantaris muscle as the result of mechanical overload; in the KI mouse, Ser209 of eIF4E was replaced with a nonphosphorylatable alanine. Contrary to our hypothesis, we observed no difference in the magnitude of hypertrophy between WT and KI groups in response to 14 days of mechanical overload induced by synergist ablation. Similarly, the increases in cyclin D1 protein levels, ribosome biogenesis, and translational capacity did not differ between WT and KI groups. Based on these findings, we conclude that phosphorylation of eIF4E at Ser209 is dispensable for skeletal muscle hypertrophy in response to mechanical overload.

Keywords: protein synthesis; ribosome biogenesis; skeletal muscle growth; translation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biomechanical Phenomena
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Eukaryotic Initiation Factor-4E / genetics*
  • Eukaryotic Initiation Factor-4E / metabolism
  • Female
  • Gene Expression Regulation
  • Gene Knock-In Techniques
  • Hypertrophy / genetics*
  • Hypertrophy / metabolism
  • Hypertrophy / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Organelle Biogenesis
  • Phosphorylation
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA, Ribosomal / genetics
  • RNA, Ribosomal / metabolism
  • Ribosomes / genetics
  • Ribosomes / metabolism
  • Serine / metabolism*
  • Signal Transduction

Substances

  • Ccnd1 protein, mouse
  • Eukaryotic Initiation Factor-4E
  • Myc protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • RNA, Ribosomal
  • eIF4E protein, mouse
  • Cyclin D1
  • Serine