Spatiotemporal control of myonuclear identity during muscle regeneration

Skeletal muscle exhibits an unusually complex architecture, in which large multinucleated myofibers accommodate a small population of resident muscle stem cells (MuSCs) along their surface. In addition, myofibers contain molecularly and functionally specialized domains at junctions with motor neurons and tendons. Regeneration of this tissue, therefore, requires a coordinated series of events, spanning MuSC activation, proliferation, fusion to restore myofiber mass, as well as reconstruction of specialized domains. Recent advances have begun to reveal how myogenic nuclei undergo dynamic state transitions in response to interactions with surrounding cell types, and how these states can be remodeled during regeneration. Here, we discuss emerging principles of myonuclear plasticity and spatial specialization.