TNF-alpha regulates myogenesis and muscle regeneration by activating p38 MAPK |
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Authors: | Chen Shuen-Ei Jin Bingwen Li Yi-Ping |
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Institution: | Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. |
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Abstract: | 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 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 medium 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 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 TNF- release 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 TNF- regulates myogenesis and muscle regeneration as a key activator of p38. myocyte enhancer factor-2C; myogenin; p21; myosin heavy chain; Akt; tumor necrosis factor-; mitogen-activated protein kinase |
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