Related Experiment Video
Updated: Jul 12, 2025
Performing Human Skeletal Muscle Xenografts in Immunodeficient Mice
Published on: September 16, 2019
Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD
Christopher D Sarsons1, Dean Gilham1, Laura M Tsujikawa1
1Resverlogix Corp., 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada.
Abstract:
Facioscapulohumeral dystrophy (FSHD) is a muscle disease caused by inappropriate expression of the double homeobox 4 (DUX4) gene in skeletal muscle, and its downstream activation of pro-apoptotic transcriptional programs. Inhibitors of DUX4 expression have the potential to treat FSHD. Apabetalone is a clinical-stage bromodomain and extra-terminal (BET) inhibitor, selective for the second bromodomain on BET proteins. Using primary human skeletal muscle cells from FSHD type 1 patients, we evaluated apabetalone for its ability to counter DUX4's deleterious effects and compared it with the pan-BET inhibitor JQ1, and the p38 MAPK inhibitor-and DUX4 transcriptional repressor-losmapimod. We applied RNA-sequencing and bioinformatic analysis to detect treatment-associated impacts on the transcriptome of these cells. Apabetalone inhibited the expression of DUX4 downstream markers, reversing hallmarks of FSHD gene expression in differentiated muscle cells. JQ1, but not apabetalone, was found to induce apoptosis. While both BET inhibitors modestly impacted differentiation marker expression, they did not affect myotube fusion. Losmapimod also reduced expression of DUX4 target genes but differed in its impact on FSHD-associated pathways. These findings demonstrate that apabetalone inhibits DUX4 target gene expression and reverses transcriptional programs that contribute to FSHD pathology, making this drug a promising candidate therapeutic for FSHD.
Insights
Apabetalone, a BET inhibitor, reversed key gene expression changes in facioscapulohumeral dystrophy (FSHD) muscle cells by targeting the DUX4 gene. This shows apabetalone
Area of Science:
- Muscle Diseases
- Genetics
- Pharmacology
Background:
- Facioscapulohumeral dystrophy (FSHD) is a genetic muscle disorder.
- FSHD is characterized by the inappropriate expression of the DUX4 gene.
- DUX4 expression activates pro-apoptotic pathways, contributing to muscle pathology.
Purpose of the Study:
- To evaluate apabetalone, a selective BET inhibitor, as a potential therapeutic for FSHD.
- To compare apabetalone's effects with JQ1 (pan-BET inhibitor) and losmapimod (p38 MAPK inhibitor).
- To assess the impact of these inhibitors on DUX4-driven gene expression and muscle cell pathology.
Main Methods:
- Primary human skeletal muscle cells from FSHD type 1 patients were used.
- Cells were treated with apabetalone, JQ1, or losmapimod.
- RNA-sequencing and bioinformatic analysis were performed to study transcriptional changes.
Main Results:
- Apabetalone inhibited DUX4 downstream markers and reversed FSHD-associated gene expression.
- JQ1 induced apoptosis, while apabetalone did not.
- Both BET inhibitors had minor effects on differentiation markers and myotube fusion; losmapimod also reduced DUX4 target genes.
Conclusions:
- Apabetalone effectively inhibits DUX4 target gene expression in FSHD muscle cells.
- Apabetalone reverses transcriptional programs contributing to FSHD pathology.
- Apabetalone represents a promising therapeutic candidate for treating FSHD.
