Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice
Genetic ablation of complement C3 attenuates muscle pathology in dysferlin-deficient mice
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DOI：
10.1172/jci42390
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发表时间：
2010-12-01
影响因子：
15.9
通讯作者：
Campbelll, Kevin P.
中科院分区：
文献类型：
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作者：
Han, Renzhi;Frett, Ellie M.;Campbelll, Kevin P.
dysferlin基因的突变是一组常染色体隐性肌肉萎缩性疾病的基础，称为dysferlin病。Dysferlin已被证明在肌肉膜修复和肌肉再生中发挥作用，这两者都需要囊泡-膜融合。然而，在这些疾病中肌肉变得营养不良的机制仍然知之甚少。尽管肌肉炎症在dysferlin病中被广泛认识，并且dysferlin在免疫细胞中表达，但免疫系统对dysferlin病病理学的贡献仍有待充分探索。在这里，我们表明，补体系统在dysferlin病的肌肉病理中起着重要的作用。Dysferlin缺乏导致肌肉中补体因子表达增加，而肌肉特异性dysferlin转基因表达使补体因子表达正常化，并消除了dysferlin缺失小鼠中存在的营养不良表型。此外，补体系统的中心组分（C3）的遗传破坏改善了dysferlin缺陷小鼠的肌肉病理学，但在遗传上不同的肌营养不良模型mdx小鼠中没有显著的有益作用。这些结果表明补体介导的肌肉损伤是dysferlin病发病机制的核心，并表明靶向补体系统可能作为这种疾病的治疗方法。
Mutations in the dysferlin gene underlie a group of autosomal recessive muscle-wasting disorders denoted as dysferlinopathies. Dysferlin has been shown to play roles in muscle membrane repair and muscle regeneration, both of which require vesicle-membrane fusion. However, the mechanism by which muscle becomes dystrophic in these disorders remains poorly understood. Although muscle inflammation is widely recognized in dysferlinopathy and dysferlin is expressed in immune cells, the contribution of the immune system to the pathology of dysferlinopathy remains to be fully explored. Here, we show that the complement system plays an important role in muscle pathology in dysferlinopathy. Dysferlin deficiency led to increased expression of complement factors in muscle, while muscle-specific transgenic expression of dysferlin normalized the expression of complement factors and eliminated the dystrophic phenotype present in dysferlin-null mice. Furthermore, genetic disruption of the central component (C3) of the complement system ameliorated muscle pathology in dysferlin-deficient mice but had no significant beneficial effect in a genetically distinct model of muscular dystrophy, mdx mice. These results demonstrate that complement-mediated muscle injury is central to the pathogenesis of dysferlinopathy and suggest that targeting the complement system might serve as a therapeutic approach for this disease.