Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B
Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B
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DOI：
10.2353/ajpath.2009.080930
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发表时间：
2009-12-01
影响因子：
6
通讯作者：
Shultz, Leonard D.
中科院分区：
文献类型：
--
作者：
Chase, Thomas H.;Cox, Gregory A.;Shultz, Leonard D.
肢带型肌营养不良症211、Miyoslil肌病和胫骨前肌远端肌病是由基因决定的dysferlin缺乏引起的严重衰弱性肌营养不良症。在这些肌营养不良症中，受损的是质膜的修复，而不是结构。尽管对dysferlin缺乏在骨骼肌中的作用了解很多，但对dysferlin在维持心肌细胞中的作用知之甚少。最近的证据表明，dysferlin缺乏会影响心肌，在压力下导致心肌病。然而，dysferlin在心肌细胞中的形态学位置和疾病随年龄的进展均未知。在这项研究中，我们研究了小鼠模型dysferlin病，使用光学和电子显微镜，以及超声心动图和意识心电图。我们确定dysferfin通常定位于心肌细胞的闰盘和肌浆。在没有dysferlin的情况下，心肌细胞膜损伤发生，并定位于闰盘和肌浆。这种损伤导致10个月大时短暂的功能缺陷，但是，与骨骼肌不同，这种细胞损伤是亚致死性的，即使在高龄也只会引起轻度心肌病。(Am J Pathol 2009，175：2299-2308; DOI：10.2353/ajpath.2009.080930）
Limb-girdle muscular dystrophy 211, Miyoslil myopathy, and distal myopathy of anterior tibialis are severely debilitating muscular dystrophies caused by genetically determined dysferlin deficiency. in these muscular dystrophies, it is the repair, not the structure, of the plasma membrane that is impaired. Though much is known about the effects of dysferlin deficiency in skeletal muscle, little is known about die role of dysferlin in maintenance of cardiomyocytes. Recent evidence suggests that dysferlin deficiency affects cardiac muscle, leading to cardiomyopathy when stressed. However, neither the morphological location of dysferlin in the cardiomyocyte nor the progression of the disease with age are known. In this study, we examined a mouse model of dysferlinopathy using light and electron microscopy as well as echocardiography and conscious electrocardiography. We determined that dysferfin is normally localized to the intercalated disk and sarcoplasm of the cardiomyocytes. in the absence of dysferlin, cardioinyocyte membrane damage occurs and is localized to the intercalated disk and sarcoplasm. This damage results in transient functional deficits at 10 months of age, but, unlike in skeletal muscle, the cell injury is sublethal and causes only mild cardiomyopathy even atadvancedages. (Am J Pathol 2009, 175:2299-2308; DOI: 10.2353/ajpath.2009.080930)