GSK-3beta inhibitors reduce protein degradation in muscles from septic rats and in dexamethasone-treated myotubes.
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.
Evenson
Amy R
AR
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue ST919, Boston, MA 02215, USA.
Fareed
Moin U
MU
Menconi
Michael J
MJ
Mitchell
Jamie C
JC
Hasselgren
Per-Olof
PO
D000818:Animals; D002478:Cells, Cultured; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000187:drug effects / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism*; D013830:Thiadiazoles / Q000494:pharmacology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000187:drug effects / Q000378:metabolism
C494356:4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione; D004791:Enzyme Inhibitors; D009124:Muscle Proteins; D012333:RNA, Messenger; D013830:Thiadiazoles; D000070584:Tripartite Motif Proteins; D003907:Dexamethasone; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride