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
  • Stress, Physiological/genetics
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • Zebrafish/genetics*
  • Antioxidants/pharmacology
  • Acetylcysteine/pharmacology
  • Arrhythmias, Cardiac/drug therapy
  • Arrhythmias, Cardiac/etiology
  • Arrhythmias, Cardiac/metabolism*
  • Cardiomyopathies/genetics
  • Cardiomyopathies/physiopathology
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Gene Expression Regulation
  • Transcription Factors/genetics*
  • Transcription Factors/metabolism
  • Larva/drug effects
  • Mitochondria, Heart/genetics
  • Mitochondria, Heart/metabolism
  • Mitochondria, Heart/pathology
  • Cardiac Conduction System Disease/etiology
  • Cardiac Conduction System Disease/genetics
  • Electrocardiography
  • Animals
  • Sarcomeres/genetics
  • Sarcomeres/metabolism*
  • Sarcomeres/pathology
(all 27)
PubMed
31704768 Full text @ Proc. Natl. Acad. Sci. USA
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
Figures
Figure Gallery (3 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
bns176
    Indel
    bns292
      Small Deletion
      s974TgTransgenic Insertion
        sd10TgTransgenic Insertion
          sd11TgTransgenic Insertion
            ups6
              Indel
              uto54TgTransgenic Insertion
                zf3074TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  No data available
                  Fish
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  GFPEFGGFP
                  mKate2EFGmKate2
                  roGFPEFGroGFP
                  1 - 4 of 4
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                  Mapping
                  No data available