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

• Published in: The international journal of biochemistry & cell biology Vol. 37; no. 10; pp. 2226 - 2238
• Main Authors: Evenson, Amy R, Fareed, Moin U, Menconi, Michael J, Mitchell, Jamie C, Hasselgren, Per-Olof
• Format: Journal Article
• Language: English
• Published: Netherlands 01.10.2005
• Subjects: 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; Rats; Rats, Sprague-Dawley; RNA, Messenger - drug effects; RNA, Messenger - metabolism; Sepsis - metabolism; SKP Cullin F-Box Protein Ligases - drug effects; SKP Cullin F-Box Protein Ligases - metabolism; Thiadiazoles - pharmacology; Tripartite Motif Proteins; Ubiquitin-Protein Ligases - drug effects; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1357-2725

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.