期刊
AMERICAN JOURNAL OF PATHOLOGY
卷 178, 期 5, 页码 2224-2235出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2011.01.054
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资金
- Institut National de la Sante et de la Recherche Medicale
- Centre National de la Recherche Scientifique
- University of Strasbourg
- College de France
- Association Francaise contre les Myopathies
- Fondation pour la Recherche Medicale [DEQ20071210538]
- Agence Nationale de la Recherche (ANR) [07-0065, 08-005]
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 mis-localization, 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. (Am J Pathol 2011, 178:2224-2235; DOI: 10.1016/j.ajpath.2011.01.054)
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