title: Increased expression of wild-type or a centronuclear myopathy mutant of dynamin 2 in skeletal muscle of adult mice leads to structural defects and muscle weakness.
abstract: Dynamin 2 (DNM2) is a large GTPase implicated in many cellular functions, including cytoskeleton regulation and endocytosis. Although 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 (peripheral nerve). To gain insight into the function of DNM2 in skeletal muscle and the pathological mechanisms leading to ADCNM, we introduced wild-type DNM2 (WT-DNM2) or R465W DNM2 (RW-DNM2), the most common ADCNM mutation, into adult wild-type mouse skeletal muscle by intramuscular adeno-associated virus injections. We detected altered localization of RW-DNM2 in mouse muscle. Several ADCNM features were present in RW-DNM2 mice: fiber 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 biopsy specimens 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 show the RW-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. Therefore, DNM2 plays important roles in the maintenance of adult muscle fibers.
authors.affiliation: Department of Translational Medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
authors.forename: Belinda S
authors.initials: BS
authors.lastname: Cowling
authors.forename: Anne
authors.initials: A
authors.lastname: Toussaint
authors.forename: Leonela
authors.initials: L
authors.lastname: Amoasii
authors.forename: Pascale
authors.initials: P
authors.lastname: Koebel
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.forename: Laurianne
authors.initials: L
authors.lastname: Davignon
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mandel
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Laporte
mesh_terms: D000818:Animals; D015153:Blotting, Western; D034285:Dynamin II / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D018908:Muscle Weakness / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic
chemical_list: D034285:Dynamin II