Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation

Antoine Muchir,Young Kim,Wei Wu,Jason C Choi,Sarah A Reilly,Howard J Worman

doi:10.1186/2044-5040-3-17

Abstract

BackgroundAutosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, move variable skeletal muscle involvement can be present. Previously, we demonstrated increased activity of extracellular signal-regulated kinase (ERK) 1/2 in hearts of LmnaH222P/H222P mice, a model of autosomal Emery-Dreifuss muscular dystrophy, and that blocking its activation improved cardiac function. We therefore examined the role of ERK1/2 activity in skeletal muscle pathology.MethodsSections of skeletal muscle from LmnaH222P/H222P mice were stained with hematoxylin and eosin and histological analysis performed using light microscopy. ERK1/2 activity was assessed in mouse tissue and cultured cells by immunoblotting and real-time polymerase chain reaction to measure expression of downstream target genes. LmnaH222P/H222P mice were treated with selumetinib, which blocks mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 that activates ERK1/2, from 16 to 20 weeks of age to assess the effects of treatment on muscle histology, ERK1/2 activity and limb grip strength.ResultsWe detected enhanced activation of ERK1/2 in skeletal muscle of LmnaH222P/H222P mice. Treatment with selumetinib ameliorated skeletal muscle histopathology and reduced serum creatine phosphokinase and aspartate aminotransferase activities. Selumetinib treatment also improved muscle function as assessed by in vivo grip strength testing.ConclusionsOur results show that ERK1/2 plays a role in the development of skeletal muscle pathology in LmnaH222/H222P mice. They further provide the first evidence that a small molecule drug may be beneficial for skeletal muscle in autosomal Emery-Dreifuss muscular dystrophy.

Highlights

Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope
We have previously shown that LmnaH222P/H222P mice have increased activity of the mitogen-activated protein kinase extracellular signal-regulated kinase (ERK) 1/2 in cardiac muscle [24]
While these results strongly suggest that abnormal ERK1/2 activation contributes to the development of cardiomyopathy in LmnaH222P/H222P mice, its pathogenic role in affected skeletal muscles is unknown

Summary

Introduction

Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Emery-Dreifuss muscular dystrophy (EDMD) is classically characterized clinically by a triad of: (1) slowly progressive muscle weakness and wasting in a scapulo-humeroperoneal distribution; (2) early contractures of the elbows, ankles, and posterior neck; and (3) dilated cardiomyopathy with conduction defects [1,2]. While the classical EDMD phenotype was first attributed to EMD and LMNA mutations, it is apparent that the same mutations in these genes can cause dilated cardiomyopathy with more variable skeletal muscle involvement [6,9,15,16,17,18,19,20,21]. LMNA mutations (different than those leading to myopathy) can cause partial lipodystrophy, peripheral neuropathy, or accelerated aging disorders such as Hutchinson-Gilford progeria syndrome [22]

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