Duchenne muscular dystrophy, a developmental disease

Description

Abstract

Duchenne muscular dystrophy (DMD) is a recessive X-linked monogenic myopathy. Mutations in the dystrophin gene result in a progressive, yet severe muscle wasting as death occurs around 30. DMD boys are currently diagnosed around 4 – an age at which muscles have already suffered. Moreover, no treatment can currently stop this disease and efficacy of developing human therapies aiming at restoring the expression of dystrophin stays too low. Our group has identified Dp412e, an embryonic isoform of dystrophin, leading us to investigate DMD during skeletal muscle development by modelling it with human induced pluripotent stem cells (hiPSCs). Our multi-omics study of the differentiation dynamics strongly argues for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, where mitochondria play an initial role and fibrosis is an intrinsic cell feature of skeletal muscle cells. It also demonstrates that hiPSCs 1) recapitulate key developmental steps, enabling the identification of early disease markers; 2) are suitable for studying skeletal myogenesis in human, in both healthy and disease contexts; and 3) are compatible with high-throughput experiments, thus increasing the capability of drug screening.