GSK-3beta inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone-treated myotubes

Int J Biochem Cell Biol. 2005 Oct;37(10):2226-38. doi: 10.1016/j.biocel.2005.06.002.


Sepsis is associated with muscle wasting, mainly reflecting increased muscle proteolysis. Recent studies suggest that inhibition of GSK-3beta activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3beta inhibitors LiCl and TDZD-8 would reduce sepsis-induced muscle proteolysis. Because muscle wasting during sepsis is, at least in part, mediated by glucocorticoids, we also tested the effects of GSK-3beta inhibitors on protein degradation in dexamethasone-treated cultured myotubes. Treatment of incubated extensor digitorum longus muscles with LiCl or TDZD-8 reduced basal and sepsis-induced protein breakdown rates. When cultured myotubes were treated with LiCl or one of the GSK-3beta inhibitors SB216763 or SB415286, protein degradation was reduced. Treatment of incubated muscles or cultured myotubes with LiCl, but not the other GSK-3beta inhibitors, resulted in increased phosphorylation of GSK-3beta at Ser9, consistent with inactivation of the kinase and suggesting that the other inhibitors used in the present experiments inhibit GSK-3beta by phosphorylation-independent mechanisms. The present results suggest that GSK-3beta inhibitors may be used to prevent or treat sepsis-induced, glucocorticoid-regulated muscle proteolysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dexamethasone / metabolism
  • Dexamethasone / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Lithium Chloride / pharmacology
  • Male
  • Muscle Fibers, Skeletal / drug effects*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Proteins / drug effects
  • Muscle Proteins / metabolism
  • Muscle, Skeletal
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • SKP Cullin F-Box Protein Ligases / drug effects
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Sepsis / metabolism*
  • Thiadiazoles / pharmacology
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases / drug effects
  • Ubiquitin-Protein Ligases / metabolism


  • 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
  • Enzyme Inhibitors
  • Muscle Proteins
  • RNA, Messenger
  • Thiadiazoles
  • Tripartite Motif Proteins
  • Dexamethasone
  • Fbxo32 protein, rat
  • SKP Cullin F-Box Protein Ligases
  • TRIM63 protein, human
  • Ubiquitin-Protein Ligases
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3
  • Lithium Chloride