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

Anaïs Fongy,Marc Bitoun,Jeanne Lainé,Sestina Falcone,Aurea Martins-Bach,Bernard Prudhon

doi:10.1038/s41598-018-38184-0

Abstract

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-Dnm2R465W/+) develops a myopathy sharing similarities with human disease. Using isolated muscle fibres from Knock In-Dnm2R465W/+ 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.

Highlights

The autosomal dominant centronuclear myopathy (CNM, OMIM 160150) is a rare congenital myopathy characterized by progressive muscle weakness and wasting usually beginning in late childhood or adolescence[1]
These results highlight the importance of Dynamin 2 (DNM2) in muscle homeostasis and extend the pathomechanisms in dominant centronuclear myopathy leading to muscle atrophy
A 3-fold increase in the mass of the Tibialis anterior (TA) muscle occurred during the same period of time in the WT mice whereas hypotrophy was noticed in HTZ TA

Summary

Introduction

The autosomal dominant centronuclear myopathy (CNM, OMIM 160150) is a rare congenital myopathy characterized by progressive muscle weakness and wasting usually beginning in late childhood or adolescence[1]. Based on biochemical and structural studies, it was suggested that CNM-related DNM2 mutations may lead to aberrant DNM2 oligomerization at abnormal cellular sites or prevent helix disassembly after GTP hydrolysis by stabilizing the oligomerized DNM210. These data argue for a potential dominant negative effect of the DNM2 mutants. We demonstrate that number of myonuclei and satellite cell content are impacted in the KI-Dnm[2] mice These results highlight the importance of DNM2 in muscle homeostasis and extend the pathomechanisms in dominant centronuclear myopathy leading to muscle atrophy

Methods

Results

Conclusion