P04

Mutations in the DMD gene lead to Duchenne muscular dystrophy (DMD), a severe X-linked neuromuscular disorder. DMD is diagnosed after 2 to 4 years but early studies indicated that symptoms are already detected in neonates and initiate before birth. This poses a serious challenge in the optimization of standards of care for DMD patients, as the disease goes unnoticed during the first years of life and possibly leads to irreparable damage in muscle tissues. Therefore, it is crucial to determine the earliest disease phenotypes and investigate the functions of the DMD gene during embryogenesis. Here, we used human induced pluripotent stem cells (hiPSCs) to recapitulate the successive steps of myogenesis in a dish and determine the developmental dynamics of DMD. We first established the single-cell trajectory followed by hiPSCs in the course of their differentiation into the skeletal muscle lineage and we showed that DMD mutant cells bifurcate towards an alternative transcriptomic endpoint when they reach the “somite” developmental stage. Here, dystrophin deficiency results in marked dysregulations of genes involved in the formation of tight junctions, adherens junctions and desmosomes. As a result, DMD cells showed an altered ability to form epithelial islets expressing somite markers and an increased motility, suggesting that dystrophin might impair the regulation of cell junction remodelling during the cell state transitions associated with somite development and delamination. Altogether, our work demonstrates that dystrophin deficiency has early consequences during myogenic development, which should be considered in future therapeutic approaches for DMD.