Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype
Transgenic overexpression of caveolin-3 in skeletal muscle fibers induces a Duchenne-like muscular dystrophy phenotype
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DOI：
10.1073/pnas.160249097
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发表时间：
2000-08-15
影响因子：
11.1
通讯作者：
Lisanti, MP
中科院分区：
文献类型：
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作者：
Galbiati, F;Volonté, D;Lisanti, MP
最近报道，杜氏肌营养不良症（DMD）患者和mdx小鼠在其骨骼肌中具有升高水平的小窝蛋白-3表达。然而，DMD患者中增加的小窝蛋白-3水平是否有助于DMD的发病机制仍然未知。在这里，我们使用遗传方法，通过在小鼠中过表达野生型小窝蛋白-3作为转基因来直接测试这一假设，对过表达小窝蛋白-3转基因小鼠的骨骼肌组织的分析表明：（i）肌膜肌细胞小窝数量急剧增加;（ii）具有特征性中央核的肥大、坏死和未成熟/再生骨骼肌纤维占优势;和（iii）肌营养不良蛋白和β-肌营养不良聚糖蛋白表达的下调。此外，这些小鼠显示血清肌酸激酶水平升高，与形态学观察到的肌坏死一致。Caveolin-3转基因小鼠的Duchenne样表型将为了解人类DMD的发病机制提供重要的小鼠模型。
It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expression in their skeletal muscle. However, it remains unknown whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of DMD. Here, using a genetic approach, we test this hypothesis directly by overexpressing wild-type caveolin-3 as a transgene in mice, Analysis of skeletal muscle tissue from caveolin-3- overexpressing transgenic mice reveals: (i) a dramatic increase in the number of sarcolemmal muscle cell caveolae; (ii) a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and (iii) down-regulation of dystrophin and beta-dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase revels, consistent with the myo-necrosis observed morphologically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans.