Skeletal muscle atrophy, a link between depression of protein synthesis and increase in degradation.
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 (eIF2alpha). 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 eIF2alpha 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, PKRDelta6. Myotubes expressing PKRDelta6 showed no increase in eIF2alpha 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-kappaB (NF-kappaB). Inhibition of PKR prevented nuclear migration of NF-kappaB in response to both PIF and angiotensin II, by preventing degradation of the inhibitor protein I-kappaB. Phosphorylation of PKR and eIF2alpha 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.
Eley
Helen L
HL
Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, United Kingdom.
Tisdale
Michael J
MJ
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011509:Proteoglycans / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000502:physiology
D015852:Eukaryotic Initiation Factor-2; D009124:Muscle Proteins; D016328:NF-kappa B; D011509:Proteoglycans; C042057:proteolysis-inducing peptide; D000804:Angiotensin II; D019892:eIF-2 Kinase