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

Bosnakovski, Darko and Chan, Sunny and Recht, Olivia and Hartweck, Lynn M. and Gustafson, Collin and Athman, Laura and Lowe, Dawn and Kyba, Michael (2017) Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nature Communications.

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Official URL: http://www.nature.com/articles/s41467-017-00730-1

Abstract

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.

Item Type: Article
Subjects: Medical and Health Sciences > Basic medicine
Divisions: Faculty of Medical Science
Depositing User: Darko Bosnakovski
Date Deposited: 05 Feb 2018 12:45
Last Modified: 05 Feb 2018 12:45
URI: http://eprints.ugd.edu.mk/id/eprint/19325

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