TNF- regulates myogenesis and muscle regeneration by activating p38 MAPK

2006; doi:10.1152/ajpcell.00486.2006.—Although p38 MAPK activa-tion is essential for myogenesis, the upstream signaling mechanism that activates p38 during myogenesis remains undefined. We recently re-ported that p38 activation, myogenesis, and regeneration in cardiotoxin-injured soleus muscle are impaired in TNF- receptor double-knockout (p55/p75/) mice. To fully evaluate the role of TNF- in 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 TNF- release from C2C12 or mouse primary myoblasts placed in low-serum differentiation medium. A TNF--neutralizing antibody added to differentiation me-dium blocked p38 activation and suppressed differentiation markers myocyte enhancer factor (MEF)-2C, myogenin, p21, and myosin heavy chain in C2C12 myoblasts. Conversely, recombinant TNF- added to