TNF-alpha regulates myogenesis and muscle regeneration by activating p38 MAPK

• Published in: American Journal of Physiology: Cell Physiology Vol. 292; no. 5; pp. C1660 - C1671
• Main Authors: Chen, Shuen-Ei, Jin, Bingwen, Li, Yi-Ping
• Format: Journal Article
• Language: English
• Published: United States 01.05.2007
• Subjects: Animals; Autocrine Communication; Cell Differentiation; Cell Line; Cobra Cardiotoxin Proteins; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; MAP Kinase Kinase 6 - metabolism; Mice; Mice, Knockout; Muscle Development - drug effects; Muscle Fibers, Skeletal - metabolism; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Muscular Diseases - chemically induced; Muscular Diseases - metabolism; Muscular Diseases - physiopathology; Myoblasts - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Receptors, Tumor Necrosis Factor, Type I - deficiency; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Receptors, Tumor Necrosis Factor, Type II - deficiency; Receptors, Tumor Necrosis Factor, Type II - genetics; Receptors, Tumor Necrosis Factor, Type II - metabolism; Regeneration - drug effects; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0363-6143; 1522-1563
• 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 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.