Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane
Dysferlin stabilizes stress-induced Ca2+ signaling in the transverse tubule membrane
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DOI：
10.1073/pnas.1307960110
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发表时间：
2013-12-17
影响因子：
11.1
通讯作者：
Bloch, Robert J.
中科院分区：
文献类型：
--
作者：
Kerr, Jaclyn P.;Ziman, Andrew P.;Bloch, Robert J.
异常铁蛋白病，最常见的四肢带状肌营养不良2B和三好肌病，是由编码异常铁蛋白的DYSF基因突变引起的退行性肌病。对异铁素的研究主要集中在其在骨骼肌肌膜修复中的作用，但异铁素与横（t-）小管中的钙（Ca2+）信号蛋白的关联表明其具有其他作用。在这里，我们发现异铁蛋白在成熟骨骼肌纤维的t小管膜中富集。在体外实验膜应激后，dysferlin缺陷的肌纤维经历t小管的广泛功能和结构破坏，这可以通过减少外部[Ca2+]或用地尔硫卓阻断l型Ca2+通道来改善。此外，我们证明，地尔硫卓治疗异常蛋白缺陷小鼠可显著减少偏心收缩引起的t小管损伤、炎症和坏死，从而导致损伤后功能恢复的增加。我们发现dysferlin是一种稳定应激诱导的Ca2+信号的t小管蛋白，为肢体带状肌营养不良2B和三好肌病患者提供了治疗途径。
Dysferlinopathies, most commonly limb girdle muscular dystrophy 2B and Miyoshi myopathy, are degenerative myopathies caused by mutations in the DYSF gene encoding the protein dysferlin. Studies of dysferlin have focused on its role in the repair of the sarcolemma of skeletal muscle, but dysferlin's association with calcium (Ca2+) signaling proteins in the transverse (t-) tubules suggests additional roles. Here, we reveal that dysferlin is enriched in the t-tubule membrane of mature skeletal muscle fibers. Following experimental membrane stress in vitro, dysferlin-deficient muscle fibers undergo extensive functional and structural disruption of the t-tubules that is ameliorated by reducing external [Ca2+] or blocking L-type Ca2+ channels with diltiazem. Furthermore, we demonstrate that diltiazem treatment of dysferlin-deficient mice significantly reduces eccentric contraction-induced t-tubule damage, inflammation, and necrosis, which resulted in a concomitant increase in postinjury functional recovery. Our discovery of dysferlin as a t-tubule protein that stabilizes stress-induced Ca2+ signaling offers a therapeutic avenue for limb girdle muscular dystrophy 2B and Miyoshi myopathy patients.