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Persistent Fibroadipogenic Progenitor Expansion Following Transient DUX4 Expression Provokes a Profibrotic State in a
Darko Bosnakovski1,2, David Oyler1,2, Ana Mitanoska1,2
1Lillehei Heart Institute, 312 Church St. SE, Minneapolis, MN 55455, USA.
Abstract:
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.
Insights
Muscle regeneration after DUX4 gene expression is possible, but past DUX4 exposure leads to lasting fibrosis. This suggests long-term cellular changes in muscle tissue, impacting potential therapies for FSHD.
Area of Science:
- Muscle biology
- Regenerative medicine
- Genetic disorders
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) is linked to DUX4 gene dysregulation.
- DUX4 protein presence in FSHD muscle biopsies remains elusive, suggesting early expression events.
- Understanding muscle regeneration after DUX4 insult is crucial for disease progression insights.
Purpose of the Study:
- To investigate muscle regeneration capacity following DUX4-mediated degeneration.
- To assess the long-term effects of DUX4 expression on muscle cellularity and fibrosis.
- To explore the implications of these findings for FSHD therapeutic strategies.
Main Methods:
- Utilized a mouse model (iDUX4pA;HSA) with inducible and reversible DUX4 expression.
- Analyzed muscle histology and cytological parameters after controlled DUX4 expression periods.
- Evaluated fibroadipogenic progenitor cell compartment and fibrosis propensity after DUX4 exposure and subsequent injury.
Main Results:
- Muscle histology significantly recovered after DUX4 expression cessation, with recovery inversely proportional to expression duration.
- The fibroadipogenic progenitor compartment remained elevated post-DUX4 expression, even after histological recovery.
- Recovered muscle exhibited increased susceptibility to severe fibrosis upon secondary injury, indicating persistent pro-fibrotic alterations.
Conclusions:
- Muscle can regenerate substantially from DUX4-induced damage, but not completely.
- Past DUX4 expression induces lasting changes in muscle cellular physiology, promoting fibrosis.
- These findings highlight the importance of addressing pro-fibrotic alterations in potential FSHD therapies.
