Muscular dystrophies are characterized by muscle weakness and degeneration induced by genetic mutation of muscle structure or signaling components. The development of treatments against dystrophies is challenging, in part due to various primary genetic defects affecting different cellular functions. Nonetheless, many studies observed mitochondrial dysfonctions in muscle pathologies. Moreover, using a worm model of Duchenne Muscular Dystrophy (DMD) our team clearly demonstrated an implication of the mitochondrial key effectors Dynamin Related Protein-1, (DRP-1) and cytochrome c in the early process of muscle degeneration (MD). We are now focusing on Reactive Oxygen Species (ROS) and Programmed Cell Death (PCD) pathways to identify common mitochondrial disorders that contribute to MD in muscular dystrophies. We established different C. elegans models that mimic human muscular dystrophies such as Duchenne and Becker dystrophies, Limb-Girdle, Emery-Dreifuss or congenital muscular dystrophy. We revealed in the C. elegans model for DMD that MD can be reduced by treatments with the mitohormetic compound Paraquat (0,1mM) or the antioxidant compounds NAC and vitamin C. This observation suggested that ROS pathways mediated by mitochondria could be targets to reduce MD. In addition, our preliminary results indicate that these treatments are also efficient against MD in other C. elegans models for human muscular dystrophies. Moreover, using a gain of function mutation in the anti-apoptotic effector
ced-9 gene (ortholog of Bcl-2) and RNA interference of key molecular actors of PCD linked to mitochondria:
ced-3,
ced-4,
ced-13 and
egl-1, we investigated whether specific mitochondrial PCD pathways are involved in MD. To validate our data obtained in C. elegans, we use human immortalized myoblasts from healthy or DMD patients. Preliminary data indicated that DMD myoblasts proliferate less and have a reduced fusion capacity during myogenic differentiation than myoblasts from healthy patients. Ongoing investigations examine mitochondrial pathways identified in C. elegans by challenging myoblasts for proliferation, cell fusion and oxidative stress sensibility.Our original approach using both worm models and human myoblasts, will allow us to establish whether manipulating mitochondrial pathways, particularly ROS signaling and PCD pathways can reduce progression of MD in muscular dystrophies.