Journal
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
Volume 37, Issue 10, Pages 2226-2238Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.biocel.2005.06.002
Keywords
muscle wasting; proteolysis; sepsis; glucocorticoids; GSK-3 beta inhibitors
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Funding
- NIDDK NIH HHS [T32-DK07754, DK37908] Funding Source: Medline
- NINR NIH HHS [NR8545] Funding Source: Medline
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Sepsis is associated with muscle wasting, mainly reflecting increased muscle proteolysis. Recent studies suggest that inhibition of GSK-3 beta activity may counteract catabolic stimuli in skeletal muscle. We tested the hypothesis that treatment of muscles from septic rats with the GSK-3 beta 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-3 beta 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-3 beta inhibitors SB216763 or SB415286, protein degradation was reduced. Treatment of incubated muscles or cultured myotubes with LiCl, but not the other GSK-3 beta inhibitors, resulted in increased phosphorylation of GSK-3 beta at Ser9, consistent with inactivation of the kinase and suggesting that the other inhibitors used in the present experiments inhibit GSK-30 by phosphorylation-independent mechanisms. The present results suggest that GSK-3 beta inhibitors may be used to prevent or treat sepsis-induced, glucocorticoid-regulated muscle proteolysis. (c) 2005 Elsevier Ltd. All rights reserved.
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