Muscular dystrophies (MD) are rare genetic disorders characterized by progressive muscle degeneration leading to muscle weakness and muscle waste. More than 72 different MD have been described so far and have been linked to primary genetic perturbations affecting 46 different genes. While the different forms of MD have a low percentage of incidences in the general population, collectively, these diseases affect many patients worldwide. Therapeutic strategies aiming at restoring the function of the implicated genes (gene and cell therapies) are very encouraging but not applicable in a near future to the variety of MDs.
The primary defects that cause muscle degenerative diseases are affecting distinct cellular pathways; accordingly, there is a large variability in clinical pathology and onset. However, these diseases can be encompassed by their unifying muscle cell death phenotype. However, no extensive comparative studies of a large panel of MDs have been carried out thus far.
We have shown that the nematode C. elegansis a useful tool to study the cellular mechanisms involved in muscle degeneration. Using a C. elegansmodel for Duchenne MD we showed that mitochondrial dynamics and apoptotic pathways plays a key role in dystrophin-dependent muscle degeneration. We also observed issues in autophagy and proteostasis. Moreover, large-scale screens in the C. elegansDMD model allowed identifying genetic and pharmacologic suppressors of dystrophin-dependent muscle degeneration; some of them positively impact mitochondrial functions or structure under stress conditions, or are involved in signaling pathways linked to mitochondria, and others are associated to proteostasis pathways such as autophagy, proteasome and Unfolded Protein Response (UPR).
Our initial comparative analysis – performed on library of 19 C. elegansmodels (including 7 models for human muscular dystrophies) – suggested the existence of some shared cellular consequences to various primary genetic defects causing muscle degeneration. This prompted us to characterize in more detail shared mechanisms and pathways and to target them with genetic and pharmacologic means so as to identify some broadly efficient suppressors of muscle degeneration. By performing comparative studies in complementary models (C. elegansand human muscle biopsies), we expect that our results will contribute to a better understanding of the mechanisms involved in human MDs and that the mechanisms and suppressors, which we will discover, will be instrumental towards the development of efficient palliative treatments for human MDs.
Our project is constructed along 4 axes:
UCBL – CNRS UMR 5310 – INSERM U1217
Faculté de Médecine et de Pharmacie – 3ème étage – Aile D
8 avenue Rockefeller