Résumé :
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Dynamin 2 (DNM2) is a large GTPase implicated in many cellular functions including cytoskeleton regulation and endocytosis. Whilst ubiquitously expressed, DNM2 was found mutated in two genetic disorders affecting different tissues: Autosomal Dominant Centronuclear Myopathy (ADCNM; skeletal muscle) and peripheral Charcot-Marie- Tooth neuropathy (CMTDIB; peripheral nerve). To gain insight into the function of DNM2 in skeletal muscle and the pathological mechanisms leading to ADCNM, we introduced DNM2 wild-type or R465W (RW-DNM2), the most common ADCNM mutation, into adult wild-type mouse skeletal muscle by intramuscular Adeno-Associated Virus (AAV) injections. We detected altered localization of RW-DNM2 in mouse muscle. Several ADCNM features were present in RW-DNM2 mice; fibre atrophy, nuclear mislocalization, and altered mitochondrial staining, with a corresponding reduction in specific maximal muscle force. The sarcomere and triad structures were also altered. We report similar findings in muscle biopsies from an ADCNM patient with the R465W mutation. In addition, expression of wild-type DNM2 induced some muscle defects, albeit to a lesser extent than RW-DNM2, suggesting that the R465W mutation has enhanced activity in vivo. In conclusion we showed the R465W DNM2 mutation acts in a dominant manner to cause ADCNM in adult muscle, and the disease arises from a primary defect in skeletal muscle rather than secondary to peripheral nerve involvement. Dynamin 2 may therefore play important roles in maintenance of adult muscle fibres.
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