期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 289, 期 5, 页码 C1179-C1187出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00062.2005
关键词
tumor necrosis factor-alpha receptor double-knockout mice; myogenesis; p38 mitogen-activated protein kinase; dystrophic calcification; contractility
资金
- NHLBI NIH HHS [R01 HL059878, HL-59878] Funding Source: Medline
- NIAMS NIH HHS [R01 AR049022-02, R01 AR049022, AR-049022] Funding Source: Medline
Recent data suggest a physiological role for the proinflammatory cytokine TNF-alpha in skeletal muscle regeneration. However, the underlying mechanism is not understood. In the present study, we analyzed TNF-alpha-activated signaling pathways involved in myogenesis in soleus muscle injured by cardiotoxin (CTX) in TNF-alpha 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-kappa 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-alpha 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-alpha signaling plays a critical regulatory role in muscle regeneration.
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