PUBLICATION
Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model
- Authors
- Collins, M.M., Ahlberg, G., Hansen, C.V., Guenther, S., Marín-Juez, R., Sokol, A.M., El-Sammak, H., Piesker, J., Hellsten, Y., Olesen, M.S., Stainier, D.Y.R., Lundegaard, P.R.
- ID
- ZDB-PUB-191111-6
- Date
- 2019
- Source
- Proceedings of the National Academy of Sciences of the United States of America 116(48): 24115-24121 (Journal)
- Registered Authors
- Lundegaard, Pia Rengtved, Marín-Juez, Rubén, Stainier, Didier
- Keywords
- cardiac development, cardiac metabolism, cardiomyopathy, transcriptional profiling
- Datasets
- GEO:GSE128511
- MeSH Terms
-
- Sarcomeres/genetics
- Sarcomeres/metabolism*
- Sarcomeres/pathology
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- Stress, Physiological/genetics
- Acetylcysteine/pharmacology
- Disease Models, Animal
- Antioxidants/pharmacology
- Mitochondria, Heart/genetics
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Animals, Genetically Modified
- Cardiac Conduction System Disease/etiology
- Cardiac Conduction System Disease/genetics
- Arrhythmias, Cardiac/drug therapy
- Arrhythmias, Cardiac/etiology
- Arrhythmias, Cardiac/metabolism*
- Cardiomyopathies/genetics
- Cardiomyopathies/physiopathology
- Gene Expression Regulation
- Electrocardiography
- Transcription Factors/genetics*
- Transcription Factors/metabolism
- Zebrafish/genetics*
- Larva/drug effects
- Animals
- PubMed
- 31704768 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Collins, M.M., Ahlberg, G., Hansen, C.V., Guenther, S., Marín-Juez, R., Sokol, A.M., El-Sammak, H., Piesker, J., Hellsten, Y., Olesen, M.S., Stainier, D.Y.R., Lundegaard, P.R. (2019) Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model. Proceedings of the National Academy of Sciences of the United States of America. 116(48):24115-24121.
Abstract
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of PITX2, a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of pitx2c in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of pitx2c+/- fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of pitx2c loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of pitx2c-/- larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping