PUBLICATION

Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy

Authors

Waugh, T.A., Horstick, E., Hur, J., Jackson, S.W., Davidson, A.E., Li, X., Dowling, J.J.

ID

ZDB-PUB-140513-91

Date

2014

Source

Human molecular genetics 23(17): 4651-62 (Journal)

Registered Authors

Dowling, Jim, Waugh, Trent

Keywords

none

MeSH Terms

Homeostasis/drug effects
Morpholinos/pharmacology
Base Sequence
Embryo, Nonmammalian/drug effects
Embryo, Nonmammalian/metabolism
Serotonin Plasma Membrane Transport Proteins/metabolism
Molecular Sequence Data
Stress, Mechanical
Survival Analysis
Dystrophin/metabolism
Disease Models, Animal
Evans Blue/metabolism
Muscular Dystrophy, Duchenne/drug therapy*
Muscular Dystrophy, Duchenne/genetics
Muscular Dystrophy, Duchenne/pathology
Animals
Calcium/metabolism
Phenotype
Oligonucleotide Array Sequence Analysis
Muscular Dystrophy, Animal/drug therapy*
Muscular Dystrophy, Animal/genetics
Muscular Dystrophy, Animal/pathology
Zebrafish/embryology
Zebrafish/genetics
Zebrafish/physiology*
Birefringence
Gene Expression Profiling
Drug Evaluation, Preclinical
Fluoxetine/pharmacology
Fluoxetine/therapeutic use*
Gene Knockdown Techniques

(all 31)

PubMed

24760771 Full text @ Hum. Mol. Genet.

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.

Genes / Markers

Figures

Show all Figures

Expression

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: fluoxetine	Prim-5 to Protruding-mouth	musculoskeletal movement occurrence, normal	Fig. S1
WT	chemical treatment: fluoxetine	Prim-5 to Protruding-mouth	swimming occurrence, normal	Fig. S1
WT	chemical treatment: fluoxetine	Day 4	intracellular calcium ion homeostasis process quality, abnormal	Fig. 8
WT	chemical treatment: fluoxetine	Protruding-mouth to Day 6	musculoskeletal movement occurrence, normal	Fig. S1
WT	chemical treatment: fluoxetine	Protruding-mouth to Day 6	swimming occurrence, normal	Fig. S1
WT	chemical treatment: fluoxetine	Days 7-13	myotome skeletal muscle myofibril organized, normal	Fig. S3
WT	chemical treatment: fluoxetine	Days 7-13	skeletal myofibril assembly process quality, normal	Fig. S3
dmd^{ta222a/ta222a}	control	Day 4	myotome skeletal muscle myofibril disorganized, abnormal	Fig. 3
dmd^{ta222a/ta222a}	control	Day 4	myotome skeletal muscle myofibril disorganized, abnormal	Fig. 4
dmd^{ta222a/ta222a}	control	Day 4	myotome skeletal muscle myofibril increased fragility, abnormal	Fig. 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ta222a		Point Mutation	dmd

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
slc6a4a	MO1-slc6a4a	MRPHLNO
slc6a4b	MO1-slc6a4b	MRPHLNO

Fish

Fish
dmd^{ta222a/ta222a}
dmd^{ta222a/ta222a} + MO1-slc6a4a
dmd^{ta222a/ta222a} + MO1-slc6a4b
WT

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Waugh et al., 2014 ZDB-PUB-140513-91 PMID:24760771

Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy

Waugh et al., 2014

ZDB-PUB-140513-91
PMID:24760771