Mechanism of activation of dsRNA-dependent protein kinase (PKR) in muscle atrophy

H.L. Eley, S.T. Russell, M.J. Tisdale

Research output: Contribution to journalArticle

Abstract

The role of Ca2+ in the activation of PKR (double-stranded-RNA-dependent protein kinase), which leads to skeletal muscle atrophy, has been investigated in murine myotubes using the cell-permeable Ca2+ chelator BAPTA/AM (1,2-bis (o-aminphenoxy) ethane-N,N,N',N'-tetraacetic acid tetra (acetoxymethyl) ester). BAPTA/AM effectively attenuated both the increase in total protein degradation, through the ubiquitin–proteasome pathway, and the depression of protein synthesis, induced by both proteolysis-inducing factor (PIF) and angiotensin II (Ang  II). Since both protein synthesis and degradation were attenuated this suggests the involvement of PKR. Indeed BAPTA/AM attenuated both the activation  (autophosphorylation) of PKR and the subsequent phosphorylation of eIF2a (eukaryotic initiation factor 2a) in the presence of PIF, suggesting the involvement of Ca2+ in this process. PIF also induced an increase in the activity of both caspases-3 and -8, which was attenuated by BAPTA/AM. The increase in caspase-3 and -8 activity was shown to be responsible for the activation of PKR, since the latter was completely attenuated by the specific caspase-3 and -8 inhibitors. These results suggest that Ca2+ is involved in the increase in protein degradation and decrease in protein synthesis by PIF and Ang II through activation of PKR by caspases-3 and -8.

Original languageEnglish
Pages (from-to)783-790
Number of pages8
JournalCellular Signalling
Volume22
Issue number5
DOIs
Publication statusPublished - 13 Jan 2010

Keywords

  • muscle atrophy
  • double-stranded-RNA-dependent protein kinase (PKR)
  • Ca2+ chelation
  • caspases-3 and -8
  • protein synthesis
  • protein degradation

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