Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration.
Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration.
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DOI：
10.1038/s41467-022-34806-4
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发表时间：
2022-11-18
影响因子：
16.6
通讯作者：
Cote, Jean-Francois
中科院分区：
文献类型：
--
作者：
Tran, Viviane;Nahle, Sarah;Robert, Amelie;Desanlis, Ines;Killoran, Ryan;Ehresmann, Sophie;Thibault, Marie-Pier;Barford, David;Ravichandran, Kodi S.;Sauvageau, Martin;Smith, Matthew J.;Kmita, Marie;Cote, Jean-Francois
成肌细胞融合是多核肌纤维发育的基础。成肌细胞融合所需的进化保守蛋白包括RAC 1及其激活剂DOCK 1。在目前的研究中，我们分析了DOCK 1相互作用的埃尔莫支架蛋白对成肌细胞融合的贡献。当Elmo 1 −/−小鼠接受肌肉特异性Elmo 2基因消融时，它们表现出严重的成肌细胞融合缺陷。Elmo 2基因的突变减少了信号传导，导致成肌细胞融合减少。相反，编码开放构象蛋白的Elmo 2突变增加了发育和肌肉再生过程中的成肌细胞融合。最后，我们发现，Dysferlin基因敲除小鼠（2B型肢带型肌营养不良症模型）的营养不良特征在以开放构象表达ELMO 2时逆转。这些数据提供了直接的证据表明，成肌细胞融合过程可以用于再生目的，并改善肌肉疾病的结果。成肌细胞融合是多核肌纤维发育的必要条件。在这里，作者表明，埃尔莫1和Elmo 2的消融损害小鼠成肌细胞融合，并且Elmo 2的开放构象的表达促进肌肉再生并改善Dysferlin缺失的营养不良小鼠的表型。
Myoblast fusion is fundamental for the development of multinucleated myofibers. Evolutionarily conserved proteins required for myoblast fusion include RAC1 and its activator DOCK1. In the current study we analyzed the contribution of the DOCK1-interacting ELMO scaffold proteins to myoblast fusion. When Elmo1−/− mice underwent muscle-specific Elmo2 genetic ablation, they exhibited severe myoblast fusion defects. A mutation in the Elmo2 gene that reduced signaling resulted in a decrease in myoblast fusion. Conversely, a mutation in Elmo2 coding for a protein with an open conformation increased myoblast fusion during development and in muscle regeneration. Finally, we showed that the dystrophic features of the Dysferlin-null mice, a model of limb-girdle muscular dystrophy type 2B, were reversed when expressing ELMO2 in an open conformation. These data provide direct evidence that the myoblast fusion process could be exploited for regenerative purposes and improve the outcome of muscle diseases. Myoblast fusion is essential for development of multinucleated myofibers. Here, the authors show that ablation of Elmo 1 and Elmo2 impairs myoblast fusion in mice, and that expression of an open conformation of Elmo2 promotes muscle regeneration and improves the phenotype of Dysferlin-null dystrophic mice.
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影响因子：
3.5
作者：
Demonbreun, Alexis R.;Fahrenbach, John P.;McNally, Elizabeth M.
通讯作者：
McNally, Elizabeth M.
影响因子：
7.8
作者：
Chuang, Mei-Chun;Lin, Shan-Shan;Liu, Ya-Wen
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Liu, Ya-Wen
影响因子：
21.3
作者：
Côté, JF;Motoyama, AB;Vuori, K
通讯作者：
Vuori, K
DOI：
10.1073/pnas.1313886111
发表时间：
2014-03-11
影响因子：
11.1
作者：
Hamoud, Noumeira;Tran, Viviane;Cote, Jean-Francois
通讯作者：
Cote, Jean-Francois
影响因子：
16.6
作者：
Chang, Leifu;Yang, Jing;Barford, David
通讯作者：
Barford, David