Résumé :
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Muscle degeneration is a progressive process, which ultimately leads to muscle cell death. It can be induced by many different primary genetic defects. We use the genetic model organism Caenorhabditis elegans to investigate the process of muscle degeneration at a sub-cellular level and to identify genetic and molecular inhibitors of this process.The C.elegans striated body wall muscle is similar to vertebrate skeletal muscle in terms of function and structural components; however, the overall architecture is less complex. In addition, the worm has invariant development: each worm possesses the same number of non-fused mono-nucleated muscle cells (there are exactly 95 striated body wall muscles). As C.elegans lacks satellite cells and therefore regenerative capabilities, each cell can be individually followed throughout its whole life, and muscle degeneration can be quantified. Moreover, C.elegans is an excellent model for electron microscopy, thus muscle morphology and intracellular events occurring during degeneration can be observed at the highest resolution. Here, we present the sub-cellular characterisation of dystrophin-dependent muscle degeneration in C.elegans. We analysed the progression of muscle degeneration from early larval stages to adulthood using electron microscopy. In addition to in depth observations and 3D reconstructions, we performed statistical analysis on measures from these electronmicrographs to identify the first sub-cellular defects and to investigate the pathogenesis of muscle degeneration occurring in dystrophic muscles at high resolution. In these studies we identified different sub-cellular compartments such as muscle cell adhesion structures, the mitochondria and the endoplasmic reticulum to be affected during muscle degeneration. Moreover, we observed the appearance of vesicles and autophagosome-like structures during the degenerative process. Sub-cellular markers were used to confirm the nature of the affected compartments and vesicle structures and to follow their profile throughout the development in worms. Starting from this study, we will now be able 1) to compare the sub-cellular process of muscle degeneration in C.elegans models for different muscular dystrophies and 2) to analyse how previously identified genetic and molecular suppressors interfere with the process of muscle degeneration.
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