Hypoxia inhibits newt skeletal muscle dedifferentiation

Abstract

Unlike mammals, newts are able to regenerate lost muscle tissue by dedifferentiating postmitotic muscle cells, which re-enter the cell cycle to form myogenic progenitors. This ability is considered central to the process of limb regeneration, yet the mechanisms underlying it remain poorly understood. Here, we leverage high-resolution time course bulk transcriptomics profiling to characterise molecular changes during differentiation and dedifferentiation of newt myotubes. We uncover that myogenesis is accompanied by a metabolic shift from glycolysis to OXPHOS, which is partially reverted upon dedifferentiation. By analysing early events during dedifferentiation, we identify TGF{beta} and members of the oxygen-responsive HIF family as putative plasticity inducers. We detect a stark, transient upregulation of HIF3A early during dedifferentiation, followed by a gradual downregulation of HIF2A. Finally, we show that hypoxia inhibits myotube cell cycle re-entry. These data provide a valuable resource to identify regulators of cellular plasticity and offer insights into the impact of oxygen signalling in regenerative processes.