Studying onset of Duchenne muscular dystrophy during myogenesis from human pluripotent stem cells to identify early markers and therapeutic targets

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. It is a recessive X-linked monogenic myopathy caused by mutations in the dystrophin gene leading to the loss of a functional protein. Most DMD patients display severe phenotypes that usually appear in early childhood (2-5 years old). These patients, one boy on 3,300 boy births, have a progressive loss of muscle strength implying the use of wheelchair by age 12 and leading to premature death due to cardiac and respiratory failures in their late twenties.

The main role of the muscle long dystrophin isoform is to maintain the homeostasis of adult muscle fibres by participating to membrane stability during contraction. Many converging data and our recent discovery of the existence of an embryonic form of dystrophin specific to the early stage of differentiation in anthropoids lead to propose new functions of this protein during the onset of skeletal muscle differentiation.
Combining the use of cell models derived from human pluripotent stem cells which mimic the earlier phases of differentiation with the exhaustive expression analysis by next-generation-sequencing approaches, our team has been able to show that DMD cells present a specific and complex phenotype from 3 days of differentiation. More precisely, we have been able to identify around 300 genes significantly dysregulated in DMD skeletal muscle progenitors. A part of these genes are associated with cell cycle, mTOR pathways, amino acid metabolism, extracellular matrix organisation and mitochondrial functions. Numerous studies described dysfunctions of many aspects of metabolism in DMD patients. Clearly, metabolisms are an important player in the DMD pathology. This aspect will be explored, in our cell models, by functional and pharmacological approaches.
From the analysis of high-throughput sequencing data, the postdoctoral researcher will elaborate novel hypotheses on the DMD phenotype during the early phases of development that will be tested in vitro by functional approaches such as gain- and loss-of-function experiments. The goal is to find DMD early markers and/or novel therapeutic targets complementary to the dystrophin rescue. This project should lead us to rethink the dystrophin function(s) during human myogenic differentiation.

Genopole-Evry is launching a new call for applications, the objective of which is to grant a fellowship intended to facilitate the return to France of a young researcher trained in France who has completed at least one post-doctoral internship abroad in order to accompany a research project within the Genopole biocluster.
This fellowship is strictly for the sole purpose of:
-A young French or foreign researchers trained in France. i. e. who have obtained their doctorate in France or who have completed at least 3 years of higher education in France.
-And who wish to return to France after a stay abroad.