Production of muscular dystrophy mice by molecular engineering

caveolin -3是caveolin蛋白家族的肌肉特异性亚型，是大多数细胞类型中发现的小泡膜内陷的主要成分。小窝蛋白在小窝膜的形成中发挥重要作用，作为支架蛋白组织和浓缩脂质修饰的信号分子，调节信号通路。例如，caveolin-3与神经元一氧化氮合成酶（nNOS）相互作用并抑制其催化活性。通过syntrophin-nNOS连接，caveolin-3也与糖异常复合物相互作用，糖异常复合物是肌细胞粘附于层粘连蛋白的主要参与者。最近，包括Pro104Leu错义突变在内的caveolin-3基因的特异性突变已被证明可导致常染色体显性肢带肌营养不良症（LGMD1C），其特征是肌膜中caveolin-3的缺乏。然而，这些突变导致小窝蛋白-3缺乏和肌肉细胞变性的分子机制仍然是难以捉摸的。在这里，我们产生了表达Pro104Leu突变体caveolin-3的转基因小鼠。他们表现出严重的肌病，并伴有肌膜中小窝蛋白-3的缺乏，表明突变小窝蛋白-3的主要负面影响。有趣的是，我们发现骨骼肌中nNOS活性大幅增加，我们认为这可能在小窝蛋白-3的肌肉纤维变性中起作用。

Caveolin-3 is the muscle-specific isoform of the caveolin protein family, which is a major component of caveolae, small membrane invaginations found in most cell types. Caveolins play important roles in the formation of caveola membranes, acting as scaffolding proteins to organize and concentrate lipid-modified signaling molecules, and modulate a signaling pathway. For instance, caveolin-3 interacts with neuronal nitric-oxide synthase (nNOS) and inhibits its catalytic activity. Via the syntrophin-nNOS linkage, caveolin-3 also interacts with the dystroglycan complex, which is a major player of muscle cell adhesion to laminin. Recently, specific mutations in the caveolin-3 gene, including the Pro104Leu missense mutation, have been shown to cause an autosomal dominant limb-girdle muscular dystrophy (LGMD1C), which is characterized by the deficiency of caveolin-3 in the sarcolemma. However, the molecular mechanism by which these mutations cause the deficiency of caveolin-3 and muscle cell degeneration remains elusive. Here we generated transgenic mice expressing the Pro104Leu mutant caveolin-3. They showed severe myopathy accompanied by the deficiency of caveolin-3 in the sarcolemma, indicating a dominant negative effect of mutant caveolin-3. Interestingly, we found a great increase of nNOS activity in their skeletal muscle, which, we propose, may play a role in muscle fiber degeneration in caveolin-3.