Skeletal muscle dedifferentiation requires centrosomes

Abstract Multinucleated skeletal muscle cells are stably withdrawn from the cell cycle in most vertebrates. Muscle dedifferentiation, however, naturally occurs during limb regeneration in newts and can be experimentally induced in mammalian myotubes. Here we addressed the dynamics of centrosomes, which are key organelles for cell proliferation during myogenic differentiation and dedifferentiation in a cross-species comparative setting. We show that, unlike their mammalian counterparts, newt muscle cells retain centrosomes during differentiation, and their abrogation during regeneration interferes with myogenic dedifferentiation as well as blastema formation in newts. Mammalian myotubes, which are experimentally induced to dedifferentiate, give rise to progeny that regain centrosomes through a process that depends on inhibition of the tumor suppressor, p53. We also find that regulation of the subcellular localization of Polo-Like Kinase 4, rather than its expression level, is a hallmark of myogenic differentiation and dedifferentiation, revealing a novel cellular process underlying the plasticity of the differentiated state.