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

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 fou...

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Published in:Nature communications 2017-09, Vol.8 (1), p.550-9, Article 550
Main Authors: Bosnakovski, Darko, Chan, Sunny S. K., Recht, Olivia O., Hartweck, Lynn M., Gustafson, Collin J., Athman, Laura L., Lowe, Dawn A., Kyba, Michael
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description 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. Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology.
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subjects 631/136/1425
692/617/375/374
692/698/1671/1668/1973
Animals
Biocompatibility
Biomedical materials
Disease Models, Animal
Doxycycline
Dystrophy
Female
Fibrosis
Gene silencing
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Human pathology
Humanities and Social Sciences
Humans
In vivo methods and tests
Low level
Male
Mice
multidisciplinary
Muscle, Skeletal - metabolism
Muscle, Skeletal - pathology
Muscular dystrophy
Muscular Dystrophy, Facioscapulohumeral - genetics
Muscular Dystrophy, Facioscapulohumeral - metabolism
Muscular Dystrophy, Facioscapulohumeral - pathology
Myopathy
Pathology
Phenotype
Polyadenylation
Regeneration
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Science
Science (multidisciplinary)
Skeletal muscle
Stochasticity
Surgical implants
title Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model
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