TNF- regulates myogenesis and muscle regeneration by activating p38 MAPK

Chen S-E, Jin B, Li Y-P. TNFregulates myogenesis and muscle regeneration by activating p38 MAPK. Am J Physiol Cell Physiol 292: C1660 –C1671, 2007. First published December 6, 2006; doi:10.1152/ajpcell.00486.2006.—Although p38 MAPK activation is essential for myogenesis, the upstream signaling mechanism that activates p38 during myogenesis remains undefined. We recently reported that p38 activation, myogenesis, and regeneration in cardiotoxininjured soleus muscle are impaired in TNFreceptor double-knockout (p55 / p75 / ) mice. To fully evaluate the role of TNFin myogenic activation of p38, we tried to determine whether p38 activation in differentiating myoblasts requires autocrine TNF, and whether forced activation of p38 rescues impaired myogenesis and regeneration in the p55 / p75 / soleus. We observed an increase of TNFrelease from C2C12 or mouse primary myoblasts placed in low-serum differentiation medium. A TNF-neutralizing antibody added to differentiation medium blocked p38 activation and suppressed differentiation markers myocyte enhancer factor (MEF)-2C, myogenin, p21, and myosin heavy chain in C2C12 myoblasts. Conversely, recombinant TNFadded to differentiation medium stimulated myogenesis at 0.05 ng/ml while inhibited it at 0.5 and 5 ng/ml. In addition, differentiation medium-induced p38 activation and myogenesis were compromised in primary myoblasts prepared from p55 / p75 / mice. Increased TNFrelease was also seen in cardiotoxin-injured soleus over the course of regeneration. Forced activation of p38 via the constitutive activator of p38, MKK6bE, rescued impaired myogenesis and regeneration in the cardiotoxin-injured p55 / p75 / soleus. These results indicate that TNFregulates myogenesis and muscle regeneration as a key activator of p38.