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MUSCLE CELL BIOLOGY AND CELL MOTILITY
signaling in regeneration of cardiotoxin-injured muscle
1Department of Medicine, Baylor College of Medicine, Houston, Texas; and 2Department of Physiology, University of Kentucky, Lexington, Kentucky
Submitted 15 February 2005 ; accepted in final form 25 June 2005
Recent data suggest a physiological role for the proinflammatory cytokine TNF-
in skeletal muscle regeneration. However, the underlying mechanism is not understood. In the present study, we analyzed TNF--activated signaling pathways involved in myogenesis in soleus muscle injured by cardiotoxin (CTX) in TNF- receptor double-knockout mice (p55–/–p75–/–). We found that activation of p38MAPK, which is critical for myogenesis, was blocked in CTX-injured p55–/–p75–/– soleus on day 3 postinjury when myogenic differentiation was being initiated, while activation of ERK1/2 and JNK MAPK, as well as transcription factor NF-
B, was not reduced. Consequently, the phosphorylation of transcription factor myocyte enhancer factor-2C, which is catalyzed by p38 and crucial for the expression of muscle-specific genes, was blunted. Meanwhile, expression of p38-dependent differentiation marker myogenin and p21 were suppressed. In addition, expression of cyclin D1 was fivefold that in wild-type (WT) soleus. These results suggest that myogenic differentiation is blocked or delayed in the absence of TNF- signaling. Histological studies revealed abnormalities in regenerating p55–/–p75–/– soleus. On day 5 postinjury, new myofiber formation was clearly observed in WT soleus but not in p55–/–p75–/– soleus. To the contrary, p55–/–p75–/– soleus displayed renewed inflammation and dystrophic calcification. On day 12 postinjury, the muscle architecture of WT soleus was largely restored. Yet, in p55–/–p75–/– soleus, multifocal areas of inflammation, myofiber death, and myofibers with smaller cross-sectional area were observed. Functional studies demonstrated an attenuated recovery of contractile force in injured p55–/–p75–/– soleus. These data suggest that TNF- signaling plays a critical regulatory role in muscle regeneration.
tumor necrosis factor- receptor double-knockout mice; myogenesis; p38 mitogen-activated protein kinase; dystrophic calcification; contractility
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