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Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy
Trent A Waugh1, Eric Horstick1, Junguk Hur2
1Department of Pediatrics.
Abstract:
Duchenne muscular dystrophy (DMD) is a common and relentlessly progressive muscle disease. Some interventions have been identified that modestly slow progression and prolong survival, but more meaningful therapies are lacking. The goal of this study is to identify new therapeutic pathways for DMD using a zebrafish model of the disease. To accomplish this, we performed a non-biased drug screen in sapje, a zebrafish line with a recessive nonsense mutation in dystrophin. We identified 6 positive hits (out of 640 total drugs tested) by their ability to prevent abnormal birefringence in sapje. Follow-up analyses demonstrated that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provided the most substantial benefit. Morpholino-based experimentation confirmed that modulation of the serotonin pathway alone can prevent the dystrophic phenotype, and transcriptomic analysis revealed changes in calcium homeostasis as a potential mechanism. In all, we demonstrate that monoamine agonists can prevent disease in a vertebrate model of DMD. Given the safe and widespread use of SSRIs in clinical practice, our study identifies an attractive target pathway for therapy development.
Insights
Researchers identified fluoxetine (an SSRI) as a potential therapy for Duchenne muscular dystrophy (DMD). This study in zebrafish suggests targeting the serotonin pathway may prevent DMD, offering a promising avenue for new treatments.
Area of Science:
- Biomedical Research
- Zebrafish Disease Models
- Molecular Biology
Background:
- Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disease with limited effective therapies.
- Current interventions offer modest benefits, highlighting the urgent need for novel therapeutic strategies.
Purpose of the Study:
- To discover new therapeutic pathways for Duchenne muscular dystrophy (DMD).
- To utilize a zebrafish model for unbiased drug screening to identify potential DMD treatments.
Main Methods:
- Conducted a non-biased drug screen of 640 compounds in a zebrafish model (sapje) of Duchenne muscular dystrophy.
- Identified drug candidates by their ability to correct abnormal birefringence, a hallmark of the disease.
- Validated findings using morpholino-based experiments and transcriptomic analysis to elucidate mechanisms.
Main Results:
- Identified 6 potential therapeutic compounds, with fluoxetine (a selective serotonin reuptake inhibitor/SSRI) showing the most significant benefit.
- Demonstrated that modulating the serotonin pathway alone can prevent the dystrophic phenotype in the zebrafish model.
- Transcriptomic analysis suggested altered calcium homeostasis as a potential underlying mechanism.
Conclusions:
- Monoamine agonists, including SSRIs, can prevent disease phenotypes in a vertebrate model of Duchenne muscular dystrophy.
- The serotonin pathway represents an attractive and druggable target for developing new Duchenne muscular dystrophy therapies.
- The established safety profile of SSRIs in humans makes this pathway a promising candidate for clinical translation.
