Satellite cells, or muscle stem cells, are resident somatic stem cells responsible for skeletal muscle regeneration. In resting adult muscles, the majority of satellite cells are quiescent. Upon stimulation, such as acute injury, satellite cells are activated and subsequently proliferate, differentiate, and finally fuse to form new muscle fibers. The whole process of muscle regeneration is tightly regulated. Emerging evidence indicates that alternative splicing regulates stem cell pluripotency maintenance and cell fate determination. However, the role of alternative splicing in the satellite cell, especially during the activation process, remains elusive. Here, we investigate the role of a major splicing regulator, Rbfox2, in satellite cells during muscle regeneration. We found that Rbf...[ Read more ]

Satellite cells, or muscle stem cells, are resident somatic stem cells responsible for skeletal muscle regeneration. In resting adult muscles, the majority of satellite cells are quiescent. Upon stimulation, such as acute injury, satellite cells are activated and subsequently proliferate, differentiate, and finally fuse to form new muscle fibers. The whole process of muscle regeneration is tightly regulated. Emerging evidence indicates that alternative splicing regulates stem cell pluripotency maintenance and cell fate determination. However, the role of alternative splicing in the satellite cell, especially during the activation process, remains elusive. Here, we investigate the role of a major splicing regulator, Rbfox2, in satellite cells during muscle regeneration. We found that Rbfox2 was upregulated in satellite cells upon activation. Loss of Rbfox2 impairs satellite cell activation, proliferation, and muscle regeneration. Using the in vivo fixation approach, we reveal a transitory splicing change during satellite cell activation. Rbfox2 regulates the splicing of some important genes during satellite cell activation. Moreover, Rbfox2 itself gives rise to multiple isoforms in satellite cells. The isoform switch of Rbfox2 is essential for regulating satellite cell differentiation. Collectively, our study shows that Rbfox2 is an important regulator in satellite cell function and muscle regeneration.