Résumé :
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Adipose infiltration is a characteristic common to many muscular dystrophies. In certain cases, the infiltration is such that all of the muscle fibers are replaced by adipocytes, preventing or at least limiting, the rational of gene or cell therapies. Our previous studies on denervated muscle have demonstrated an unsuspected plasticity of muscle fibres. Indeed, the muscle syncytium, reserved the capacity to convert into mononucleated cells able to develop into adipocytes. These results enable us to re-examine the physiopathology of Duchenne myopathy and the progressive emergence of adipose metaplasia. The primum movens remains the absence of dystrophin, which is at the origin of the extreme fragility of DMD muscle fibres. This fragility results in spontaneous microlesions. The number and repetition of necrotic events are such that certain microlesions probably escape the repair process thus causing the electric disconnection of distal parts of segmented fibers. These distal segments would then develop like denervated muscle, resulting in a fatty transformation. The rational mentioned above encouraged us to explore the consequences of an interruption of the functional activity of muscle fibers without affecting the nerve-muscle communication. This can be carried out by destroying the skeletal excitation-contraction coupling system. The excitation-contraction coupling is guaranteed at the level of the triads, forming “electric synapses” between membranes of the transverse tubules and the sarcoplasmic reticulum. It has been known that the alpha1s sub-unit of the slow Ca2+ channel (DHP-R) ensures the “voltage sensor”. To study the morphogenetic consequences related to an inactivation of this sensor, we have developed AAV vectors harboring constructions coding snRNA-U7 directed against exons crucial for the synthesis of the alpha1s sub-unit. Kinetics of muscle atrophy, tissue modifications and expression of molecular markers following this type of paralysis were analyzed.
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