Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
Lack of correlation between outcomes of membrane repair assay and correction of dystrophic changes in experimental therapeutic strategy in dysferlinopathy.
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DOI：
10.1371/journal.pone.0038036
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Richard I
中科院分区：
文献类型：
--
作者：
Lostal W;Bartoli M;Roudaut C;Bourg N;Krahn M;Pryadkina M;Borel P;Suel L;Roche JA;Stockholm D;Bloch RJ;Levy N;Bashir R;Richard I
异铁蛋白基因突变是2B型肢带肌营养不良症和三好肌病的病因。异常铁蛋白与肌层重封有关，导致异常铁蛋白缺乏的病理生理是由于膜修复的缺陷。在这里，我们展示了使用两种不同的方法，即激光损伤实验检测的全填充膜修复不足以减轻异种酪素缺乏的病理。首先，我们构建了一只过表达myoferlin的转基因小鼠，以验证myoferlin（与dysferlin同源）可以弥补dysferlin缺失的假设。肌铁蛋白过表达者未显示出骨骼肌异常，并且将它们与异常铁蛋白缺陷模型杂交可在体外修复异常铁蛋白缺陷小鼠的膜融合缺陷。然而，肌钙素过表达并不能在体内纠正肌肉组织学。其次，我们报道aav介导的minidysferlin的转移，先前在体外被证明可以纠正膜修复缺陷，也不能改善肌肉组织学。此外，肌钙素和微量肌钙素都不能预防偏心运动后的肌纤维变性。我们的数据表明，异常铁蛋白缺乏的致病性并不仅仅与肌上皮修复损伤有关，并强调了在选择检测方法以评估异常铁蛋白病的潜在治疗方法时需要注意。
Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea that the pathophysiology of dysferlin deficiencies is due to a deficit in membrane repair. Here, we show using two different approaches that fullfiling membrane repair as asseyed by laser wounding assay is not sufficient for alleviating the dysferlin deficient pathology. First, we generated a transgenic mouse overexpressing myoferlin to test the hypothesis that myoferlin, which is homologous to dysferlin, can compensate for the absence of dysferlin. The myoferlin overexpressors show no skeletal muscle abnormalities, and crossing them with a dysferlin-deficient model rescues the membrane fusion defect present in dysferlin-deficient mice in vitro. However, myoferlin overexpression does not correct muscle histology in vivo. Second, we report that AAV-mediated transfer of a minidysferlin, previously shown to correct the membrane repair deficit in vitro, also fails to improve muscle histology. Furthermore, neither myoferlin nor the minidysferlin prevented myofiber degeneration following eccentric exercise. Our data suggest that the pathogenicity of dysferlin deficiency is not solely related to impairment in sarcolemmal repair and highlight the care needed in selecting assays to assess potential therapies for dysferlinopathies.
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