A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice.
Autosomal dominant centronuclear myopathy (AD-CNM) is due to mutations in the gene encoding dynamin 2 (DNM2) involved in endocytosis and intracellular membrane trafficking. To understand the pathomechanisms resulting from a DNM2 mutation, we generated a knock-in mouse model expressing the most frequent AD-CNM mutation (KI-Dnm2(R465W)). Heterozygous (HTZ) mice developed a myopathy showing a specific spatial and temporal muscle involvement. In the primarily and prominently affected tibialis anterior muscle, impairment of the contractile properties was evidenced at weaning and was progressively associated with atrophy and histopathological abnormalities mainly affecting mitochondria and reticular network. Expression of genes involved in ubiquitin-proteosome and autophagy pathways was up-regulated during DNM2-induced atrophy. In isolated muscle fibers from wild-type and HTZ mice, Dnm2 localized in regions of intense membrane trafficking (I-band and perinuclear region), emphasizing the pathophysiological hypothesis in which DNM2-dependent trafficking would be altered. In addition, HTZ fibers showed an increased calcium concentration as well as an intracellular Dnm2 and dysferlin accumulation. A similar dysferlin retention, never reported so far in congenital myopathies, was also demonstrated in biopsies from DNM2-CNM patients and can be considered as a new marker to orientate direct genetic testing. Homozygous (HMZ) mice died during the first hours of life. Impairment of clathrin-mediated endocytosis, demonstrated in HMZ embryonic fibroblasts, could be the cause of lethality. Overall, this first mouse model of DNM2-related myopathy shows the crucial role of DNM2 in muscle homeostasis and will be a precious tool to study DNM2 functions in muscle, pathomechanisms of DNM2-CNM and developing therapeutic strategies.
Durieux
Anne-Cécile
AC
Université Pierre et Marie Curie-Paris 6, IFR14, Paris F-75013, France.
Vignaud
Alban
A
Prudhon
Bernard
B
Viou
Mai Thao
MT
Beuvin
Maud
M
Vassilopoulos
Stéphane
S
Fraysse
Bodvaël
B
Ferry
Arnaud
A
Lainé
Jeanne
J
Romero
Norma B
NB
Guicheney
Pascale
P
Bitoun
Marc
M
D000818:Animals; D001522:Behavior, Animal; D002118:Calcium / Q000378:metabolism; D034285:Dynamin II / Q000235:genetics*; D000073939:Dysferlin; D004622:Embryo, Mammalian / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009119:Muscle Contraction / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000473:pathology* / Q000503:physiopathology* / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D020914:Myopathies, Structural, Congenital / Q000235:genetics* / Q000503:physiopathology*; D010641:Phenotype; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism
C114839:DYSF protein, human; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins; D034285:Dynamin II; D002118:Calcium