Nuclear defects in skeletal muscle from a Dynamin 2-linked centronuclear myopathy mouse model

Dynamin 2 (DNM2) is a key protein of the endocytosis and intracellular membrane trafficking machinery. Mutations in the DNM2 gene cause autosomal dominant centronuclear myopathy (CNM) and a knock-in mouse model expressing the most frequent human DNM2 mutation in CNM (Knock In- Dnm2 R465W/+ ) develop...

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Bibliographic Details
Published in:Scientific reports 2019-02, Vol.9 (1), p.1580-1580, Article 1580
Main Authors: Fongy, Anaïs, Falcone, Sestina, Lainé, Jeanne, Prudhon, Bernard, Martins-Bach, Aurea, Bitoun, Marc
Format: Article
Language:English
Subjects:
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Atrophy
Dynamin
Endocytosis
Human health and pathology
Humanities and Social Sciences
Life Sciences
Membrane trafficking
multidisciplinary
Muscles
Mutation
Myopathy
Satellite cells
Science
Science (multidisciplinary)
Skeletal muscle
Spatial distribution
Tibialis anterior muscle
Tissues and Organs
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Summary:Dynamin 2 (DNM2) is a key protein of the endocytosis and intracellular membrane trafficking machinery. Mutations in the DNM2 gene cause autosomal dominant centronuclear myopathy (CNM) and a knock-in mouse model expressing the most frequent human DNM2 mutation in CNM (Knock In- Dnm2 R465W/+ ) develops a myopathy sharing similarities with human disease. Using isolated muscle fibres from Knock In- Dnm2 R465W/+ mice, we investigated number, spatial distribution and morphology of myonuclei. We showed a reduction of nuclear number from 20 weeks of age in Tibialis anterior muscle from heterozygous mice. This reduction is associated with a decrease in the satellite cell content in heterozygous muscles. The concomitant reduction of myonuclei number and cross-section area in the heterozygous fibres contributes to largely maintain myonuclear density and volume of myonuclear domain. Moreover, we identified signs of impaired spatial nuclear distribution including alteration of distance from myonuclei to their nearest neighbours and change in orientation of the nuclei. This study highlights reduction of number of myonuclei, a key regulator of the myofiber size, as a new pathomechanism underlying muscle atrophy in the dominant centronuclear myopathy. In addition, this study opens a new line of investigation which could prove particularly important on satellite cells in dominant centronuclear myopathy.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-38184-0