GSK-3β 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: Elsevier Ltd 01.10.2005
• Subjects: Glucocorticoids; GSK-3β inhibitors; Muscle wasting; Proteolysis; Sepsis; Sepsis; Glucocorticoids; Muscle wasting; Proteolysis; GSK-3β inhibitors
• ISSN: 1357-2725; 1878-5875
• 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-3β activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3β 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-3β 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-3β inhibitors SB216763 or SB415286, protein degradation was reduced. Treatment of incubated muscles or cultured myotubes with LiCl, but not the other GSK-3β inhibitors, resulted in increased phosphorylation of GSK-3β at Ser9, consistent with inactivation of the kinase and suggesting that the other inhibitors used in the present experiments inhibit GSK-3β by phosphorylation-independent mechanisms. The present results suggest that GSK-3β inhibitors may be used to prevent or treat sepsis-induced, glucocorticoid-regulated muscle proteolysis.