Deficiency of emerin contributes differently to the pathogenesis of skeletal and cardiac muscles in LmnaH222P/H222P mutant mice.

Eiji Wada,Wen-Chen Liang,Yukiko K Hayashi,Megumi Kato,Gisèle Bonne,Hiroko Kokuba,Kaori Yamashita,Atsushi Asakura

doi:10.1371/journal.pone.0221512

Abstract

Laminopathies are tissue-selective diseases that affect differently in organ systems. Mutations in nuclear envelopes, emerin (Emd) and lamin A/C (Lmna) genes, cause clinically indistinguishable myopathy called Emery-Dreifuss muscular dystrophy (EDMD) and limb-girdle muscular dystrophy. Several murine models for EDMD have been generated; however, emerin-null (Emd) mice do not show obvious skeletal and cardiac muscle phenotypes, and Lmna H222P/H222P mutant (H222P) mice show only a mild phenotype in skeletal muscle when they already have severe cardiomyopathy. Thus, the underlying molecular mechanism of muscle involvement due to nuclear abnormalities is still unclarified. We generated double mutant (Emd-/-/LmnaH222P/H222P; EH) mice to characterize dystrophic changes and to elucidate interactions between emerin and lamin A/C in skeletal and cardiac muscles. As H222P mice, EH mice grow normally and have breeding productivity. EH mice showed severer muscle involvement compared with that of H222P mice which was an independent of cardiac abnormality at 12 weeks of age. Nuclear abnormalities, reduced muscle fiber size and increased fibrosis were prominent in EH mice. Roles of emerin and lamin A/C in satellite cells function and regeneration of muscle fiber were also evaluated by cardiotoxin-induced muscle injury. Delayed increases in myog and myh3 expression were seen in both H222P and EH mice; however, the expression levels of those genes were similar with control and regenerated muscle fiber size was not different at day 7 after injury. These results indicate that EH mouse is a suitable model for studying skeletal muscle involvement, independent of cardiac function, in laminopathies and an interaction between emerin and lamin A/C in different tissues.

Highlights

The nuclear envelope (NE) comprises the inner and outer nuclear membranes (INM and ONM, respectively) with disassembly of nuclear pore complexes and the underlying nuclear lamina network in the inner membrane
H222P mutant (H222P), and Emd-/-/LmnaH222P/ H222P double-mutant (EH) mice were indistinguishable from wild type (WT) mice and did not show any abnormal behavior in a standard cage during their childhood
Mutations in genes encoding NE proteins result in distinct disease phenotypes; interactions of NE proteins are thought to be an important factor for understanding the tissue-specific phenotypes

Summary

Introduction

The nuclear envelope (NE) comprises the inner and outer nuclear membranes (INM and ONM, respectively) with disassembly of nuclear pore complexes and the underlying nuclear lamina network (type V intermediate filament proteins termed A-type and B-type lamins) in the inner membrane. The nuclear envelopathies are a group of disorders caused by mutations in genes encoding various nuclear envelope proteins. Mutations in EMD cause X-linked Emery-Dreifuss muscular dystrophy (EDMD) [6,7,8]. Mutations in LMNA, which encodes nuclear lamina proteins, the A-type lamins (lamins A and C, hereafter named lamin A/C), cause autosomal-dominant (AD) or less frequent recessive types of EDMD [9]. Mutations in LNMA are associated with a wide range of tissue-specific diseases called the laminopathies, including muscular dystrophy and cardiomyopathy, as well as peripheral neuropathy, familial partial lipodystrophy, and accelerated aging disorders, such as Hutchinson-Gilford progeria syndrome [13]. The underlying molecular mechanisms by which mutations in these genes encoding ubiquitously expressed NE proteins cause tissue-specific phenotypes have not been elucidated

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