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Research Article

Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model

View ORCID ProfileMichelle M. Collins, Gustav Ahlberg, Camilla Vestergaard Hansen, Stefan Guenther, Rubén Marín-Juez, Anna M. Sokol, Hadil El-Sammak, Janett Piesker, Ylva Hellsten, Morten S. Olesen, Didier Y. R. Stainier, and View ORCID ProfilePia R. Lundegaard
PNAS November 26, 2019 116 (48) 24115-24121; first published November 8, 2019; https://doi.org/10.1073/pnas.1913905116
Michelle M. Collins
aDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
bDZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;
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  • ORCID record for Michelle M. Collins
  • For correspondence: michelle.collins@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de plundegaard@sund.ku.dk
Gustav Ahlberg
cLaboratory for Molecular Cardiology, Department of Cardiology, Vascular, Pulmonary and Infectious Diseases, University Hospital of Copenhagen, 2100 Copenhagen, Denmark;
dDepartment of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
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Camilla Vestergaard Hansen
eDepartment of Nutrition, Exercise and Sport, University of Copenhagen, 2200 Copenhagen, Denmark;
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Stefan Guenther
fBioinformatics and Deep Sequencing Platform, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
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Rubén Marín-Juez
aDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
bDZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;
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Anna M. Sokol
aDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
bDZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;
gBiomolecular Mass Spectrometry, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
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Hadil El-Sammak
aDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
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Janett Piesker
hMicroscopy Service Group, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany
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Ylva Hellsten
eDepartment of Nutrition, Exercise and Sport, University of Copenhagen, 2200 Copenhagen, Denmark;
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Morten S. Olesen
cLaboratory for Molecular Cardiology, Department of Cardiology, Vascular, Pulmonary and Infectious Diseases, University Hospital of Copenhagen, 2100 Copenhagen, Denmark;
dDepartment of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
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Didier Y. R. Stainier
aDepartment of Developmental Genetics, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany;
bDZHK German Centre for Cardiovascular Research, Partner Site Rhine-Main, D-61231 Bad Nauheim, Germany;
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  • For correspondence: michelle.collins@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de plundegaard@sund.ku.dk
Pia R. Lundegaard
cLaboratory for Molecular Cardiology, Department of Cardiology, Vascular, Pulmonary and Infectious Diseases, University Hospital of Copenhagen, 2100 Copenhagen, Denmark;
dDepartment of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark;
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  • ORCID record for Pia R. Lundegaard
  • For correspondence: michelle.collins@mpi-bn.mpg.de didier.stainier@mpi-bn.mpg.de plundegaard@sund.ku.dk
  1. Edited by Calum A. MacRae, Harvard Medical School, Boston, MA, and accepted by Editorial Board Member Christine E. Seidman October 2, 2019 (received for review August 12, 2019)

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Significance

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 2 to 3% of the general population and leading to significant morbidity and mortality. Genome-wide association studies identified the 4q25 AF risk locus, a region that forms long-range interactions with the promoter of PITX2, which encodes a critical transcriptional regulator of cardiac development. Using a zebrafish pitx2c loss-of-function model, we find that larval and adult zebrafish phenocopy many hallmarks of human AF. Our data further indicate that the pathogenesis of arrhythmia and AF-like phenotypes in pitx2c mutants is driven by developmental perturbations to sarcomere organization and metabolic pathways. We also find that antioxidant treatment reduces the incidence and severity of cardiac arrhythmia, suggesting avenues for therapeutic strategies.

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.

  • cardiac development
  • cardiomyopathy
  • cardiac metabolism
  • transcriptional profiling

Footnotes

  • ↵1To whom correspondence may be addressed. Email: michelle.collins{at}mpi-bn.mpg.de, didier.stainier{at}mpi-bn.mpg.de, or plundegaard{at}sund.ku.dk.
  • Author contributions: M.M.C., M.S.O., D.Y.R.S., and P.R.L. designed research; M.M.C., C.V.H., S.G., J.P., Y.H., and P.R.L. performed research; R.M.-J., A.M.S., and H.E.-S. contributed new reagents/analytic tools; M.M.C., G.A., C.V.H., S.G., M.S.O., D.Y.R.S., and P.R.L. analyzed data; and M.M.C., D.Y.R.S., and P.R.L. wrote the paper.

  • The authors declare no competing interest.

  • This article is a PNAS Direct Submission. C.A.M. is a guest editor invited by the Editorial Board.

  • Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE128511).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1913905116/-/DCSupplemental.

Published under the PNAS license.

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Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model
Michelle M. Collins, Gustav Ahlberg, Camilla Vestergaard Hansen, Stefan Guenther, Rubén Marín-Juez, Anna M. Sokol, Hadil El-Sammak, Janett Piesker, Ylva Hellsten, Morten S. Olesen, Didier Y. R. Stainier, Pia R. Lundegaard
Proceedings of the National Academy of Sciences Nov 2019, 116 (48) 24115-24121; DOI: 10.1073/pnas.1913905116

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Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model
Michelle M. Collins, Gustav Ahlberg, Camilla Vestergaard Hansen, Stefan Guenther, Rubén Marín-Juez, Anna M. Sokol, Hadil El-Sammak, Janett Piesker, Ylva Hellsten, Morten S. Olesen, Didier Y. R. Stainier, Pia R. Lundegaard
Proceedings of the National Academy of Sciences Nov 2019, 116 (48) 24115-24121; DOI: 10.1073/pnas.1913905116
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