title: TNF-alpha regulates myogenesis and muscle regeneration by activating p38 MAPK.
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-alpha receptor double-knockout (p55(-/-)p75(-/-)) mice. To fully evaluate the role of TNF-alpha in myogenic activation of p38, we tried to determine whether p38 activation in differentiating myoblasts requires autocrine TNF-alpha, and whether forced activation of p38 rescues impaired myogenesis and regeneration in the p55(-/-)p75(-/-) soleus. We observed an increase of TNF-alpha release from C2C12 or mouse primary myoblasts placed in low-serum differentiation medium. A TNF-alpha-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-alpha 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-alpha 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-alpha regulates myogenesis and muscle regeneration as a key activator of p38.
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Shuen-Ei
authors.initials: SE
authors.lastname: Chen
authors.forename: Bingwen
authors.initials: B
authors.lastname: Jin
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002454:Cell Differentiation; D002460:Cell Line; D004179:Cobra Cardiotoxin Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D032446:Myoblasts / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D004179:Cobra Cardiotoxin Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6