(The FASEB Journal. 2005;19:362-370.)
© 2005 FASEB
TNF-
acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle
Yi-Ping Li*,1,
Yuling Chen*,
Joseph John*,
Jennifer Moylan
,
Bingwen Jin*,
Douglas L. Mann* and
Michael B. Reid,1
* Department of Medicine, Baylor College of Medicine, Houston, Texas, USA; and
Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA
1Correspondence: Y.P.L., Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; E-mail: yiping{at}bcm.tmc.edu or M.B.R., Department of Physiology, University of Kentucky Medical Center, 800 Rose St., Room MS-509, Lexington, KY 40502, USA; E-mail: michael.reid{at}uky.edu
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-
(TNF-) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF- would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF- exposure up-regulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF- increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF- 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- 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- acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.—Li, Y.-P., Chen, Y., John, J., Moylan, J., Jin, B., Mann, D. L., Reid, M. B. TNF- acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle
Key Words: tumor necrosis factor • muscle wasting • ubituitin conjugating activity
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Copyright © 2005 by The Federation of American Societies for Experimental Biology.
