Deciphering mechanisms of myoblast fusion

项目摘要/摘要 尽管成肌细胞融合对正常肌肉发育和生理很重要，但相对较少。 已知在成肌细胞融合反应中直接起重塑细胞膜功能的分子。 阐明融合机制对于充分理解肌肉发育和识别新的 加强骨骼肌疾病的治疗策略。我们先前发现myomaker(Mymk) 和Mymerger(Mymx)是骨骼肌祖细胞融合所必需的。此外，异位 这两种膜蛋白的表达可以诱导非融合细胞(成纤维细胞)的融合。为 第一次，这建立了一个基于细胞的重建系统，无论成肌细胞融合原有多少 关于这两种蛋白质是如何诱导融合的问题还存在。我们最近发现，肌动蛋白和 肌聚体通过一种独特的细胞机制，通过分裂它们独立的膜来驱动融合 重塑活动明显影响融合过程。顺理成章的是膜重塑 肌构体和肌聚体的活动必须受到高度调控，否则它们可能会 损害细胞的完整性。通过这一补充，我们将扩展我们的计划，以确定新的因素 调节骨骼肌组织的融合。总体而言，这项工作有望开辟一个新的调查领域 深入到肌肉的细胞生物学，并积极影响利用融合来提高再生能力的可能性 医药。

Project Summary/Abstract Despite the importance of myoblast fusion for normal muscle development and physiology, relatively little is known about the molecules that directly function to remodel membranes during the myoblast fusion reaction. Elucidation of fusion mechanisms is critical to fully understand muscle development and to identify novel therapeutic strategies to augment skeletal muscle disease. We previously discovered that myomaker (Mymk) and myomerger (Mymx) are essential for the fusion of skeletal muscle progenitors. Moreover, ectopic expression of these two membrane proteins induces fusion of otherwise non-fusogenic cells (fibroblasts). For the first time, this establishes a cell-based reconstitution system with myoblast fusogens, however many questions exist as to how these two proteins induce fusion. We have recently found that myomaker and myomerger drive fusion through a unique cellular mechanism, by dividing their independent membrane remodeling activities to distinctly impact the fusion process. It stands to reason that the membrane-remodeling activities of myomaker and myomerger must be highly regulated or they could have the potential to compromise cellular integrity. With this supplement, we will expand our program to identify novel factors that regulate fusion in skeletal muscle tissue. Overall, this work promises to open up a new area of investigation into the cell biology of muscle and positively impact the possibility to harness fusion to improve regenerative medicine.