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. elegans is a useful tool to study the cellular mechanisms involved in muscle degeneration. Using a C. elegans model 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. elegans DMD 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. elegans models (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. elegans and 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:
- Determination of conserved molecular mechanisms of muscle degeneration through analysis of genetic and/or pharmacologic suppressors
- Analysis of mitochondrial dynamics, unfolded protein response and apoptotic pathways during muscle degeneration
- Role and interaction of NF-κB, autophagy and other protein quality control pathways in the muscle degenerative process
- Comparative ultrastructural analysis of muscle degeneration
- DRP-1-mediated apoptosis induces muscle degeneration in dystrophin mutants
Scholtes C, Bellemin S, Martin E, Carre-Pierrat M, Mollereau B, Gieseler K, Walter L. Sci Rep (2018) May 9. 8(1):7354. doi: 10.1038/s41598-018-25727-8.
- Modulation of Protein Quality Control and Proteasome to Autophagy Switch in Immortalized Myoblasts from Duchenne Muscular Dystrophy Patients.
Wattin M, Gaweda L, Muller P, Baritaud M, Scholtes C, Lozano C, Gieseler K, Kretz-Remy C Int J Mol Sci. (2018) 19(1).
- UNC-120/SRF independently controls muscle aging and lifespan in Caenorhabditis elegans.
Mergoud Dit Lamarche A, Molin L, Pierson L, Mariol MC, Bessereau JL, Gieseler K, Solari F Aging Cell (2018) doi: 10.1111/acel.12713.
- NFκB is a central regulator of protein quality control in response to protein aggregation stresses via autophagy modulation.
Nivon M, Fort L, Muller P, Richet E, Simon S, Guey B, Fournier M, Arrigo AP, Hetz C, Atkin JD, Kretz-Remy C Mol Biol Cell (2016) Jun 1;27(11):1712-27.
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
Klionsky DJ et al. Autophagy (2016) 12(1):1-222..
- Development, structure, and maintenance of C. elegans body wall muscle.
Gieseler, K., Qadota,H., and Benian, G.M. WormBook (2016) August 23 - download PDF.
- Ultra-structural time-course study in the C. elegans model for Duchenne muscular dystrophy highlights a crucial role for sarcomere-anchoring structures and sarcolemma integrity in the earliest steps of the muscle degeneration process.
Brouilly N, Lecroisey C, Martin E, Pierson L, Mariol MC, Qadota H, Labouesse M, Streichenberger N, Mounier N, Gieseler K. Hum Mol Genet (2015) 24, 6428-45.
- Chemical genetics unveils a key role of mitochondrial dynamics, cytochrome c release and IP3R activity in muscular dystrophy.
Giacomotto J, Brouilly N, Walter L, Mariol MC, Berger J, Ségalat L, Becker TS, Currie PD, Gieseler K Hum Mol Genet (2013) 15, 4562-78.
- A Rapid Protocol for Integrating Extrachromosomal Arrays With High Transmission Rate into the C. elegans Genome.
Mariol, M. C., Walter, L., Bellemin, S., Gieseler, K. J. Vis. Exp. 2013 ((82), e50773, doi:10.3791/50773) .
- ZYX-1, the unique zyxin protein of Caenorhabditis elegans, is involved in dystrophin-dependent muscle degeneration.
Lecroisey C, Brouilly N, Qadota H, Mariol MC, Rochette NC, Martin E, Benian GM, Ségalat L, Mounier N, Gieseler K Mol Biol Cell (2013) 24, 1232-49.
- NF-κB regulates protein quality control after heat stress through modulation of BAG3/HspB8 complex.
Nivon M, Abou-Samra M, Richet E, Guyot B, Arrigo, A-P and Kretz-Remy C J Cell Sci (2012) 125, 1141-1151.
- Guidelines for the use and intepretation of assays for monitoring autophagy.
Klionsky DJ, Abdalla FC, Kretz-Remy C, Zuckerbraun B Autophagy (2012) 8, 445-544.
- Caenorhabditis elegans as a chemical screening tool for the study of neuromuscular disorders: Manual and semi-automated methods.
Giacomotto J, Ségalat L, Carre-Pierrat M, Gieseler K Methods (2012) 56, 103-13.
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