Dysferlin and Myoferlin Regulate Transverse Tubule Formation and Glycerol Sensitivity
Dysferlin and Myoferlin Regulate Transverse Tubule Formation and Glycerol Sensitivity
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DOI：
10.1016/j.ajpath.2013.09.009
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发表时间：
2014-01-01
影响因子：
6
通讯作者：
McNally, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Demonbreun, Alexis R.;Rossi, Ann E.;McNally, Elizabeth M.
Dysferlin是一种膜相关蛋白，与肌营养不良和肌肉中的囊泡运动和功能有关。dysferlin的确切作用一直存在争议，部分原因是dysferlin缺失小鼠（Dysf）的轻度表型。我们将Dysf小鼠与缺乏肌钙蛋白（MKO）的小鼠交配，以产生缺乏肌钙蛋白和dysferlin（FER）的小鼠。FER动物表现出进行性肌肉损伤，伴肌纤维坏死、细胞核内化，以及在老年时慢性重塑和肌酸激酶水平升高。这些变化在近端肢体和躯干肌肉中最为突出，并且比Dysf小鼠更严重。因此，FER动物的自由活动减少。超微结构研究发现肌浆网和异位和错位的横小管在FER骨骼肌进行性扩张。FER和Dysf小鼠的FER肌肉、Dysf和MKO缺失肌肉、渗出的脂质和血清甘油水平升高。已知甘油注射到肌肉中会诱发肌病，甘油暴露会促进横小管从肌浆网脱离。Dysf、MKO和FER肌肉在体外对甘油暴露高度敏感，表明肌小管系统功能障碍，并且在体内甘油暴露诱导严重的肌营养不良，特别是在FER肌肉中。总之，这些发现证明了dysferlin和myoferlin对横小管功能和肌营养不良症发生的重要性。
Dysferlin is a membrane-associated protein implicated in muscular dystrophy and vesicle movement and function in muscles. The precise role of dysferlin has been debated, partly because of the mild phenotype in dysferlin-null mice (Dysf). We bred Dysf mice to mice lacking myoferlin (MKO) to generate mice lacking both myoferlin and dysferlin (FER). FER animals displayed progressive muscle damage with myofiber necrosis, internalized nuclei, and, at older ages, chronic remodeling and increasing creatine kinase levels. These changes were most prominent in proximal limb and trunk muscles and were more severe than in Dysf mice. Consistently, FER animals had reduced ad libitum activity. Ultrastructural studies uncovered progressive dilation of the sarcoplasmic reticulum and ectopic and misaligned transverse tubules in FER skeletal muscle. FER muscle, and Dysf- and MKO-null muscle, exuded lipid, and serum glycerol levels were elevated in FER and Dysf mice. Glycerol injection into muscle is known to induce myopathy, and glycerol exposure promotes detachment of transverse tubules from the sarcoplasmic reticulum. Dysf, MKO, and FER muscles were highly susceptible to glycerol exposure in vitro, demonstrating a dysfunctional sarcotubule system, and in vivo glycerol exposure induced severe muscular dystrophy, especially in FER muscle. Together, these findings demonstrate the importance of dysferlin and myoferlin for transverse tubule function and in the genesis of muscular dystrophy.