title: Muscle dysfunction in a zebrafish model of Duchenne muscular dystrophy.
abstract: Sapjezebrafish lack the protein dystrophin and are the smallest vertebrate model of Duchenne muscular dystrophy (DMD). Their small size makes them ideal for large-scale drug discovery screens. However, the extent thatsapjemimic the muscle dysfunction of higher vertebrate models of DMD is unclear. We used an optical birefringence assay to differentiate affected dystrophicsapjelarvae from their unaffected siblings and then studied trunk muscle contractility at 4-7 days postfertilization. Preparation cross-sectional area (CSA) was similar for affected and unaffected larvae, yet tetanic forces of affected preparations were only 30-60% of normal. ANCOVA indicated that the linear relationship observed between tetanic force and CSA for unaffected preparations was absent in the affected population. Consequently, the average force/CSA of affected larvae was depressed 30-70%. Disproportionate reductions in twitch vs. tetanic force, and a slowing of twitch tension development and relaxation, indicated that the myofibrillar disorganization evident in the birefringence assay could not explain the entire force loss. Single eccentric contractions, in which activated preparations were lengthened 5-10%, resulted in tetanic force deficits in both groups of larvae. However, deficits of affected preparations were three- to fivefold greater at all strains and ages, even after accounting for any recovery. Based on these functional assessments, we conclude that thesapjemutant zebrafish is a phenotypically severe model of DMD. The severe contractile deficits ofsapjelarvae represent novel physiological endpoints for therapeutic drug screening.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts; jeffrey.widrick@childrens.harvard.edu.|Department of Pediatrics and Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Widrick
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.|Department of Pediatrics and Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Alexander
authors.affiliation: Department of Neurology, Division of Neuromuscular Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
authors.forename: Benjamin
authors.identifier: 0000-0002-1594-9847
authors.initials: B
authors.lastname: Sanchez
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Devin E
authors.initials: DE
authors.lastname: Gibbs
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.|Department of Pediatrics and Genetics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Genri
authors.initials: G
authors.lastname: Kawahara
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts; and.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts.|Department of Pediatrics and Genetics, Harvard Medical School, Boston, Massachusetts.|The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts; and.|Harvard Stem Cell Institute, Cambridge, Massachusetts.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007700:Kinetics; D009119:Muscle Contraction; D018656:Muscle Fibers, Fast-Twitch / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000473:pathology; D018482:Muscle, Skeletal / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000503:physiopathology*; D012044:Regression Analysis; D012518:Sarcomeres / Q000378:metabolism; D013746:Tetany / Q000503:physiopathology; D015027:Zebrafish / Q000502:physiology*
keywords: disease models; dystrophin; muscle contraction; muscular dystrophy; zebrafish