Loss of dysferlin or myoferlin results in differential defects in excitation-contraction coupling in mouse skeletal muscle.
Loss of dysferlin or myoferlin results in differential defects in excitation-contraction coupling in mouse skeletal muscle.
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DOI：
10.1038/s41598-021-95378-9
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发表时间：
2021-08-05
影响因子：
4.6
通讯作者：
Demonbreun AR
中科院分区：
文献类型：
--
作者：
Barefield DY;Sell JJ;Tahtah I;Kearns SD;McNally EM;Demonbreun AR
肌营养不良症是一种以进行性肌肉丧失和无力为特征的疾病，其基因型和表型均具有异质性。肌肉疾病的进展是由再生受损、质膜不稳定、膜修复缺陷和钙处理不当引起的。 ferlin 蛋白家族，包括 Dysferlin 和 myoferlin，是钙结合膜相关蛋白，可调节膜融合、运输和小管形成。先前证明，在同基因近交 129 背景下缺乏 Dysferlin (Dysf)、Myoferlin (Myof) 以及 Dysferlin 和 Myoferlin (Fer) 的小鼠，同时丢失 Dysferlin 和 Myoferlin 会导致比单独丢失任一基因更严重的肌肉疾病。此外，Fer 小鼠具有紊乱的三联体组织，具有明显畸形的横管和肌浆网，表明 Dysferlin 和 Myoferlin 的不同作用。为了评估无序三联征的生理作用，我们现在评估了这些模型中的兴奋收缩（EC）耦合。我们在从 ferlin 突变小鼠中分离出的指短屈肌纤维中发现了 EC 偶联和兰尼碱受体破坏的差异异常。我们发现，与野生型肌纤维相比，仅 Dysferlin 的缺失保留了 EC 偶联的敏感性，并且与更大的兰尼碱受体簇相关。与野生型肌纤维相比，肌铁蛋白单独缺失或与 Dysferlin 一起缺失会降低 EC 偶联的敏感性，并产生杂乱且较小的兰尼碱受体簇大小。这些数据揭示了 Myof 和 Fer 肌纤维中的 EC 耦合受损，以及 Dysf 肌纤维中的 EC 耦合略有增强。尽管具有高度同源性，dysferlin 和 myoferlin 在调节肌小管形成和维持方面具有不同的作用，导致钙处理特性的独特损害。
Muscular dystrophies are disorders characterized by progressive muscle loss and weakness that are both genotypically and phenotypically heterogenous. Progression of muscle disease arises from impaired regeneration, plasma membrane instability, defective membrane repair, and calcium mishandling. The ferlin protein family, including dysferlin and myoferlin, are calcium-binding, membrane-associated proteins that regulate membrane fusion, trafficking, and tubule formation. Mice lacking dysferlin (Dysf), myoferlin (Myof), and both dysferlin and myoferlin (Fer) on an isogenic inbred 129 background were previously demonstrated that loss of both dysferlin and myoferlin resulted in more severe muscle disease than loss of either gene alone. Furthermore, Fer mice had disordered triad organization with visibly malformed transverse tubules and sarcoplasmic reticulum, suggesting distinct roles of dysferlin and myoferlin. To assess the physiological role of disorganized triads, we now assessed excitation contraction (EC) coupling in these models. We identified differential abnormalities in EC coupling and ryanodine receptor disruption in flexor digitorum brevis myofibers isolated from ferlin mutant mice. We found that loss of dysferlin alone preserved sensitivity for EC coupling and was associated with larger ryanodine receptor clusters compared to wildtype myofibers. Loss of myoferlin alone or together with a loss of dysferlin reduced sensitivity for EC coupling, and produced disorganized and smaller ryanodine receptor cluster size compared to wildtype myofibers. These data reveal impaired EC coupling in Myof and Fer myofibers and slightly potentiated EC coupling in Dysf myofibers. Despite high homology, dysferlin and myoferlin have differential roles in regulating sarcotubular formation and maintenance resulting in unique impairments in calcium handling properties.
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影响因子：
6
作者：
Demonbreun, Alexis R.;Rossi, Ann E.;McNally, Elizabeth M.
通讯作者：
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影响因子：
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作者：
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通讯作者：
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作者：
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通讯作者：
Shankar, S. K.
影响因子：
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作者：
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Bushby, KMD