Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD

被引:11
|
作者
Bosnakovski, Darko [1 ,2 ]
Oyler, David [1 ,2 ]
Mitanoska, Ana [1 ,2 ]
Douglas, Madison [1 ,2 ]
Ener, Elizabeth T. [1 ,2 ]
Shams, Ahmed S. [1 ,2 ,3 ]
Kyba, Michael [1 ,2 ]
机构
[1] Lillehei Heart Inst, 312 Church St, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA
[3] Suez Canal Univ, Fac Med, Human Anat & Embryol Program, Ismailia 41111, Egypt
关键词
facioscapulohumeral muscular dystrophy; DUX4; fibroadiopgenic progenitors; fibrosis; FACIOSCAPULOHUMERAL MUSCULAR-DYSTROPHY; DNA REARRANGEMENTS; MUSCLE INJURY; D4Z4; GENE; DIFFERENTIATION; DAMAGE; LOCUS;
D O I
10.3390/ijms23041983
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
FSHD is caused by loss of silencing of the DUX4 gene, but the DUX4 protein has not yet been directly detected immunohistologically in affected muscle, raising the possibility that DUX4 expression may occur at time points prior to obtaining adult biopsies for analysis, with consequent perturbations of muscle being responsible for disease progression. To test the extent to which muscle can regenerate following DUX4-mediated degeneration, we employed an animal model with reversible DUX4 expression, the iDUX4pA;HSA mouse. We find that muscle histology does recover substantially after DUX4 expression is switched off, with the extent of recovery correlating inversely with the duration of prior DUX4 expression. However, despite fairly normal muscle histology, and recovery of most cytological parameters, the fibroadipogenic progenitor compartment, which is significantly elevated during bouts of fiber-specific DUX4 expression, does not return to basal levels, even many weeks after a single burst of DUX4 expression. We find that muscle that has recovered from a DUX4 burst acquires a propensity for severe fibrosis, which can be revealed by subsequent cardiotoxin injuries. These results suggest that a past history of DUX4 expression leads to maintained pro-fibrotic alterations in the cellular physiology of muscle, with potential implications for therapeutic approaches.
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页数:12
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