Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model

Darko Bosnakovski,Olivia O Recht,Michael Kyba,Sunny S K Chan,Lynn M Hartweck,Collin J Gustafson,Laura L Athman,Dawn A Lowe

doi:10.1038/s41467-017-00730-1

Darko Bosnakovski, Olivia O Recht + Show 6 more

Open Access

PDF Available

https://doi.org/10.1038/s41467-017-00730-1

Copy DOI

Export

Save

Cite

Abstract
Highlights/Summary
Full-Text PDF
Similar Papers

Abstract

Listen

Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression of the transcription factor DUX4; however, DUX4 expression is very low, and protein has not been detected directly in patient biopsies. Efforts to model DUX4 myopathy in mice have foundered either in being too severe, or in lacking muscle phenotypes. Here we show that the endogenous facioscapulohumeral muscular dystrophy-specific DUX4 polyadenylation signal is surprisingly inefficient, and use this finding to develop an facioscapulohumeral muscular dystrophy mouse model with muscle-specific doxycycline-regulated DUX4 expression. Very low expression levels, resulting in infrequent DUX4 + myonuclei, evoke a slow progressive degenerative myopathy. The degenerative process involves inflammation and a remarkable expansion in the fibroadipogenic progenitor compartment, leading to fibrosis. These animals also show high frequency hearing deficits and impaired skeletal muscle regeneration after injury. This mouse model will facilitate in vivo testing of therapeutics, and suggests the involvement of fibroadipogenic progenitors in facioscapulohumeral muscular dystrophy.

Highlights

Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression of the transcription factor DUX4; DUX4 expression is very low, and protein has not been detected directly in patient biopsies
We find that very low levels of DUX4 expression in skeletal muscle fibers lead to an expansion in the fibroadiopgenic progenitor compartment, and to a progressive fibrotic degeneration of skeletal muscles
By making DUX4 expression dependent on its endogenous relatively inefficient pA, we have reduced the basal off-state activity and eliminated the dominant lethality of the inducible DUX4 transgene

Summary

Introduction

Facioscapulohumeral muscular dystrophy is a slowly progressive but devastating myopathy caused by loss of repression of the transcription factor DUX4; DUX4 expression is very low, and protein has not been detected directly in patient biopsies. The degenerative process involves inflammation and a remarkable expansion in the fibroadipogenic progenitor compartment, leading to fibrosis These animals show high frequency hearing deficits and impaired skeletal muscle regeneration after injury. DUX4/D4Z4 transgenic mice have to date either lacked a muscle phenotype[19], or displayed such a strong multisystem phenotype that most die as embryos and rare live-born animals die before adult muscle develops[20] The latter mouse, named iDUX4[2.7] carried a doxycycline-inducible DUX4 gene followed by the SV40 poly A signal integrated onto the X chromosome. We find that by changing the polyadenylation signal used in this X-linked transgene, basal expression in the off state is reduced and the multisystem phenotype is ameliorated This new mouse model enables growth to adulthood and the study of muscle-specific expression of DUX4 in both males and females. We find that very low levels of DUX4 expression in skeletal muscle fibers lead to an expansion in the fibroadiopgenic progenitor compartment, and to a progressive fibrotic degeneration of skeletal muscles

Methods

Results

Conclusion