TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle.
Atrogin1/MAFbx is an ubiquitin ligase that mediates muscle atrophy in a variety of catabolic states. We recently found that H2O2 stimulates atrogin1/MAFbx gene expression. Since the cytokine tumor necrosis factor-alpha (TNF-alpha) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF-alpha would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF-alpha exposure up-regulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF-alpha increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF-alpha or H2O2 also produced general activation of the mitogen-activated protein kinases (MAPKs): p38, ERK1/2, and JNK. The increase in atrogin1/MAFbx gene expression induced by TNF-alpha was not altered significantly by ERK inhibitor PD98059 or the JNK inhibitor SP600125. In contrast, atrogin1/MAFbx up-regulation and the associated increase in ubiquitin conjugating activity were both blunted by p38 inhibitors, either SB203580 or curcumin. These data suggest that TNF-alpha acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.
Li
Yi-Ping
YP
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. yiping@bcm.tmc.edu
Chen
Yuling
Y
John
Joseph
J
Moylan
Jennifer
J
Jin
Bingwen
B
Mann
Douglas L
DL
Reid
Michael B
MB
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D009124:Muscle Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D048051:p38 Mitogen-Activated Protein Kinases
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