Department of Human Genetics, University of Utah, Salt Lake City, UT, USA.
Department of Pediatrics, Division of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Dev Cell. 2024 Jun 3;59(11):1457-1474.e5. doi: 10.1016/j.devcel.2024.03.017. Epub 2024 Apr 2.
The function of many organs, including skeletal muscle, depends on their three-dimensional structure. Muscle regeneration therefore requires not only reestablishment of myofibers but also restoration of tissue architecture. Resident muscle stem cells (SCs) are essential for regeneration, but how SCs regenerate muscle architecture is largely unknown. We address this problem using genetic labeling of mouse SCs and whole-mount imaging to reconstruct, in three dimensions, muscle regeneration. Unexpectedly, we found that myofibers form via two distinct phases of fusion and the residual basement membrane of necrotic myofibers is critical for promoting fusion and orienting regenerated myofibers. Furthermore, the centralized myonuclei characteristic of regenerated myofibers are associated with myofibrillogenesis and endure months post injury. Finally, we elucidate two cellular mechanisms for the formation of branched myofibers, a pathology characteristic of diseased muscle. We provide a synthesis of the cellular events of regeneration and show that these differ from those used during development.
许多器官的功能，包括骨骼肌，都依赖于它们的三维结构。因此，肌肉再生不仅需要重建肌纤维，还需要恢复组织架构。驻留的肌肉干细胞（SCs）对再生至关重要，但SCs 如何再生肌肉结构在很大程度上是未知的。我们使用遗传标记的小鼠 SCs 和全组织成像来解决这个问题，以三维方式重建肌肉再生。出乎意料的是，我们发现肌纤维通过融合的两个不同阶段形成，并且坏死肌纤维的残余基膜对于促进融合和定向再生肌纤维至关重要。此外，再生肌纤维特征性的集中核是与肌原纤维发生相关的，并在损伤后持续数月。最后，我们阐明了形成分支肌纤维的两种细胞机制，这是疾病肌肉的特征性病变。我们提供了再生细胞事件的综合描述，并表明这些与发育过程中使用的机制不同。
