TIMP3 regulates p38 MAPK‐dependent myogenesis via TACE

Abstract

Activation of p38 MAPK is a critical step in the onset of myogenesis. However, the upstream signaling mechanism that activates p38 during myogenesis remains undefined. We have recently found that p38 activation in differentiating myoblasts and regenerating muscle is mediated by autocrine TNF‐α release which is the function of TNF‐α converting enzyme (TACE). In the present study, we tested a hypothesis that tissue inhibitor of metallopreoteinase3 (TIMP3), the endogenous inhibitor of TACE, is a physiological suppressor of myogenesis, and is a part of the regulatory mechanism for the activation of myogenesis. We observed a dramatic down‐regulation in TIMP3 level during the first 48 h of C2C12 myoblast differentiation. Overexpression of TIMP3 suppressed TNF‐α release and blocked p38 activation, myogenin and myosin heavy chain expression, and myotube formation. Conversely, addition of recombinant TNF‐α (50 pg/ml) to differentiation medium rescued the impaired myogenesis. Down‐regulation of TIMP3 was also observed in cardiotoxin‐injured mouse soleus muscle; and overexpressed TIMP3 inhibited p38 activation and myogenesis. In addition, the down‐regulation of TIMP3 is accompanied by a decline in TIMP3 mRNA level. These results indicate that TIMP3 is a physiological suppressor of myogenesis and its down‐regulation activates p38‐dependent myogenesis.Supported by National Institute of Health Grant AR049022