Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation

Helen L. Eley, Michael J. Tisdale*

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Both proteolysis-inducing factor (PIF) and angiotensin II have been shown to produce a depression in protein synthesis in murine myotubes concomitant with an increased phosphorylation of eukaryotic initiation factor 2 (eIF2α). Both PIF and angiotensin II were shown to induce autophosphorylation of the RNA-dependent protein kinase (PKR), and an inhibitor of this enzyme completely attenuated the depression in protein synthesis and prevented the induction of eIF2α phosphorylation. The PKR inhibitor also completely attenuated the increase in protein degradation induced by PIF and angiotensin II and prevented the increase in proteasome expression and activity. To confirm these results myotubes were transfected with plasmids that express either wild-type PKR, or a catalytically inactive PKR variant, PKRΔ6. Myotubes expressing PKRΔ6 showed no increase in eIF2α phosphorylation in response to PIF or angiotensin II, no depression in protein synthesis, and no increase in protein degradation or increase in proteasome expression. Induction of the ubiquitin-proteasome pathway by PIF and angiotensin II has been linked to activation of the transcription factor nuclear factor-κB (NF-κB). Inhibition of PKR prevented nuclear migration of NF-κB in response to both PIF and angiotensin II, by preventing degradation of the inhibitor protein I-κB. Phosphorylation of PKR and eIF2α was also significantly increased in the gastrocnemius muscle of weight losing mice bearing the MAC16 tumor, suggesting that a similar process may be operative in cancer cachexia. These results provide a link between the depression of protein synthesis in skeletal muscle and the increase in protein degradation. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Original languageEnglish
Pages (from-to)7087-7097
Number of pages11
JournalJournal of Biological Chemistry
Volume282
Issue number10
DOIs
Publication statusPublished - 9 Mar 2007

Keywords

  • proteolysis-inducing factor
  • PIF
  • angiotensin II
  • protein synthesis
  • murine myotubes
  • phosphorylation
  • eukaryotic initiation factor 2
  • eIF2α
  • autophosphorylation
  • RNA-dependent protein kinase
  • PKR
  • skeletal muscle
  • protein degradation

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