Skeletal muscle fibers count on nuclear numbers for growth.

Skeletal muscle cells are noteworthy for their syncytial nature, with each myofiber accumulating hundreds or thousands of nuclei derived from resident muscle stem cells (MuSCs). These nuclei are accrued through cell fusion, which is controlled by the two essential fusogens Myomaker and Myomerger that are transiently expressed within the myogenic lineage. While the absolute requirement of fusion for muscle development has been known for decades, the underlying need for the magnitude of multinucleation in muscle remains mysterious. Possible advantages of multinucleation include the potential it affords for transcriptional diversity within these massive cells, and as a means of increasing DNA content to support optimal cell size and function. In this article, we review recent advances that elucidate the relationship between myonuclear numbers and establishment of myofiber size, and discuss how this new information refines our understanding of the concept of myonuclear domains (MND), the cytoplasmic volumes that each resident myonucleus can support. Finally, we explore the potential consequences and costs of multinucleation and its impacts on myonuclear transcriptional reserve capacity, growth potential, myofiber size regulation, and muscle adaptability. We anticipate this report will not only serve to highlight the latest advances in the basic biology of syncytial muscle cells but also provide information to help design the next generation of therapeutic strategies to maintain muscle mass and function.