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 Rengtved Lundegaard

doi:10.1073/pnas.1913905116

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 Rengtved Lundegaard^*

^*Corresponding author for this work

8 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	48
Pages (from-to)	24115-24121
Number of pages	7
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1913905116
Publication status	Published - 26 Nov 2019

Keywords

Faculty of Science
Cardiac development
Cardiomyopathy
Cardiac metabolism
Transcriptional profiling

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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. https://doi.org/10.1073/pnas.1913905116

Early sarcomere and metabolic defects in a zebrafish pitx2c cardiac arrhythmia model. / Collins, Michelle M; Ahlberg, Gustav; Hansen, Camilla Vestergaard et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 48, 26.11.2019, p. 24115-24121.

Research output: Contribution to journal › Journal article › Research › peer-review

Collins, MM, Ahlberg, G, Hansen, CV, Guenther, S, Marín-Juez, R, Sokol, AM, El-Sammak, H, Piesker, J, Hellsten, Y , Olesen, MS, Stainier, DYR & Lundegaard, PR 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, vol. 116, no. 48, pp. 24115-24121. https://doi.org/10.1073/pnas.1913905116

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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.",

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AU - Collins, Michelle M

AU - Ahlberg, Gustav

AU - Hansen, Camilla Vestergaard

AU - Guenther, Stefan

AU - Marín-Juez, Rubén

AU - Sokol, Anna M

AU - El-Sammak, Hadil

AU - Piesker, Janett

AU - Hellsten, Ylva

AU - Olesen, Morten S

AU - Stainier, Didier Y R

AU - Lundegaard, Pia Rengtved

N1 - CURIS 2019 NEXS 351

PY - 2019/11/26

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N2 - 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.

AB - 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.

KW - Faculty of Science

KW - Cardiac development

KW - Cardiomyopathy

KW - Cardiac metabolism

KW - Transcriptional profiling

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DO - 10.1073/pnas.1913905116

M3 - Journal article

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SN - 0027-8424

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EP - 24121

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 48

ER -

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

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