{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:09:32Z","timestamp":1791284972281,"version":"4.1.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"24","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2010,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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-Dnm2R465W). 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\u2013proteosome 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddq413","type":"journal-article","created":{"date-parts":[[2010,9,22]],"date-time":"2010-09-22T00:16:47Z","timestamp":1285114607000},"page":"4820-4836","source":"Crossref","is-referenced-by-count":133,"title":["A centronuclear myopathy-dynamin 2 mutation impairs skeletal muscle structure and function in mice"],"prefix":"10.1093","volume":"19","author":[{"given":"Anne-C\u00e9cile","family":"Durieux","sequence":"first","affiliation":[{"name":"\u00a0Universit\u00e9 Pierre et Marie Curie-Paris 6, IFR14, Paris F-75013, France,"},{"name":"\u00a0CNRS, \u00a0UMR 7215, Paris, France,"},{"name":"\u00a0Inserm, \u00a0U974, Paris F-75013, France,"},{"name":"\u00a0Institut de Myologie, Paris, 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