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Signaling in Regeneration of Cardiotoxin-Injured Muscle
1 Department of Medicine, Baylor College of Medicine, Houston, TX, USA
2 Department of Physiology, University of Kentuchy, Lexington, KY, USA
* To whom correspondence should be addressed. E-mail: yiping{at}bcm.tmc.edu.
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 p38 MAPK which is critical for myogenesis was blocked in CTX-injured p55-/-p75-/- soleus on day 3 post-injury when myogenic differentiation is being initiated, while activation of ERK1/2 and JNK MAPK, as well as transcription factor NF-
B was not reduced. Consequently, phosphorylation of transcription factor MEF-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 5-fold of that in wild type (WT) soleus. These results suggest that myogenic differentiation is blocked or delayed in absence of TNF- signaling. Histological study revealed abnormalities in regenerating p55-/-p75-/- soleus. On day 5 post-injury, while new myofiber formation was clearly seen in WT soleus, but not in p55-/-p75-/- soleus. On the contrary, p55-/-p75-/- soleus displayed renewed inflammation and dystrophic calcification. On day 12, muscle architecture of WT soleus was largely restored. Yet, in p55-/-p75-/- soleus, multi-focal areas of inflammation, myofiber death, and myofibers with smaller cross sectional area (XSA) were seen. 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.
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