Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD
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 o...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/4/1983 |
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| author | Darko Bosnakovski David Oyler Ana Mitanoska Madison Douglas Elizabeth T. Ener Ahmed S. Shams Michael Kyba |
| author_facet | Darko Bosnakovski David Oyler Ana Mitanoska Madison Douglas Elizabeth T. Ener Ahmed S. Shams Michael Kyba |
| author_sort | Darko Bosnakovski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T21:45:57Z |
| format | Article |
| id | doaj.art-6004c77f508143bc95c5736325e346bd |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T21:45:57Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6004c77f508143bc95c5736325e346bd2023-11-23T20:17:52ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-02-01234198310.3390/ijms23041983Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHDDarko Bosnakovski0David Oyler1Ana Mitanoska2Madison Douglas3Elizabeth T. Ener4Ahmed S. Shams5Michael Kyba6Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USALillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USALillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USALillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USALillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USALillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USALillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USAFSHD 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.https://www.mdpi.com/1422-0067/23/4/1983facioscapulohumeral muscular dystrophyDUX4fibroadiopgenic progenitorsfibrosis |
| spellingShingle | Darko Bosnakovski David Oyler Ana Mitanoska Madison Douglas Elizabeth T. Ener Ahmed S. Shams Michael Kyba Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD International Journal of Molecular Sciences facioscapulohumeral muscular dystrophy DUX4 fibroadiopgenic progenitors fibrosis |
| title | Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD |
| title_full | Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD |
| title_fullStr | Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD |
| title_full_unstemmed | Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD |
| title_short | Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a Mouse Model for FSHD |
| title_sort | persistent fibroadipogenic progenitor expansion following transient dux4 expression provokes a profibrotic state in a mouse model for fshd |
| topic | facioscapulohumeral muscular dystrophy DUX4 fibroadiopgenic progenitors fibrosis |
| url | https://www.mdpi.com/1422-0067/23/4/1983 |
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