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Nat Commun. 2017 Sep 15;8(1):550. doi: 10.1038/s41467-017-00730-1.

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

Author information

1
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, 55455, USA.
2
Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA.
3
Faculty of Medical Sciences, University Goce Delcev - Stip, Stip, 2000, Macedonia.
4
Division of Rehabilitation Science and Division of Physical Therapy, Department of Rehabilitation Medicine, University of Minnesota, Minneapolis, MN, 55455, USA.
5
Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, 55455, USA. kyba@umn.edu.
6
Department of Pediatrics, University of Minnesota, Minneapolis, MN, 55455, USA. kyba@umn.edu.

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.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.

PMID:
28916757
PMCID:
PMC5601940
DOI:
10.1038/s41467-017-00730-1
[Indexed for MEDLINE]
Free PMC Article

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