TNF‐α acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle

ABSTRACT 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‐α (TNF‐α) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF‐α would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF‐α exposure up‐regulates atrogin1/MAFbx mRNA within2hin C2C12 myotubes. Intraperitoneal injection of TNF‐α increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF‐α 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‐α 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‐α 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‐α acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J. 19, 362–370 (2005)