Metabolic modulation regulates cardiac wall morphogenesis in zebrafish

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Abstract

During cardiac development, cardiomyocytes form complex inner wall structures called trabeculae. Despite significant investigation into this process, the potential role of metabolism has not been addressed. Using single cell resolution imaging in zebrafish, we find that cardiomyocytes seeding the trabecular layer actively change their shape while compact layer cardiomyocytes remain static. We show that Erbb2 signaling, which is required for trabeculation, activates glycolysis to support changes in cardiomyocyte shape and behavior. Pharmacological inhibition of glycolysis impairs cardiac trabeculation, and cardiomyocyte-specific loss- and gain-of-function manipulations of glycolysis decrease and increase trabeculation, respectively. In addition, loss of the glycolytic enzyme pyruvate kinase M2 impairs trabeculation. Experiments with rat neonatal cardiomyocytes in culture further support these observations. Our findings reveal new roles for glycolysis in regulating cardiomyocyte behavior during cardiac wall morphogenesis.

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Most cited references 40

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Pyruvate kinase M2 is a phosphotyrosine-binding protein.

Heather Christofk, Matthew Vander Heiden, Ning Wu … (2008)

Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.

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Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.

Stephen Kolwicz, Suneet Purohit, Rong Tian (2013)

The network for cardiac fuel metabolism contains intricate sets of interacting pathways that result in both ATP-producing and non-ATP-producing end points for each class of energy substrates. The most salient feature of the network is the metabolic flexibility demonstrated in response to various stimuli, including developmental changes and nutritional status. The heart is also capable of remodeling the metabolic pathways in chronic pathophysiological conditions, which results in modulations of myocardial energetics and contractile function. In a quest to understand the complexity of the cardiac metabolic network, pharmacological and genetic tools have been engaged to manipulate cardiac metabolism in a variety of research models. In concert, a host of therapeutic interventions have been tested clinically to target substrate preference, insulin sensitivity, and mitochondrial function. In addition, the contribution of cellular metabolism to growth, survival, and other signaling pathways through the production of metabolic intermediates has been increasingly noted. In this review, we provide an overview of the cardiac metabolic network and highlight alterations observed in cardiac pathologies as well as strategies used as metabolic therapies in heart failure. Lastly, the ability of metabolic derivatives to intersect growth and survival are also discussed.

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Genetics of congenital heart disease: the glass half empty.

Akl Fahed, Bruce Gelb, J G Seidman … (2013)

Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogenesis. In contrast, the precise genetic, epigenetic, or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families, and by sequencing candidate genes in CHD cohorts. Although yielding few, usually highly penetrant, disease gene mutations, these discoveries provided 3 notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including single nucleotide polymorphism arrays, next-generation sequencing, and copy number variant platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.

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Author and article information

Contributors

Ryuichi Fukuda:

ORCID: https://orcid.org/0000-0002-0281-5161

Didier YR Stainier:

ORCID: https://orcid.org/0000-0002-0382-0026

Marianne E Bronner: Role: Reviewing Editor

Marianne E Bronner: Role: Senior Editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 23 December 2019

Publication date Collection: 2019

Volume: 8

Electronic Location Identifier: e50161

Affiliations

[1 ]deptDepartment of Developmental Genetics Max Planck Institute for Heart and Lung Research LudwigstrasseGermany

[2 ]deptDepartment of Molecular Cell Biology Weizmann Institute of Science RehovotIsrael

[3 ]deptAngiogenesis & Metabolism Laboratory Max Planck Institute for Heart and Lung Research LudwigstrasseGermany

California Institute of Technology United States

National Human Genome Research Institute United States

Author notes

[†]

Department of Physiology, Anatomy and Genetics, BHF Centre of Research Excellence, University of Oxford, Oxford, United Kingdom.

Author information

Ryuichi Fukuda https://orcid.org/0000-0002-0281-5161

Yu Ting Ong http://orcid.org/0000-0003-3407-2515

Eldad Tzahor http://orcid.org/0000-0002-5212-9426

Didier YR Stainier https://orcid.org/0000-0002-0382-0026

Article

Publisher ID: 50161

DOI: 10.7554/eLife.50161

PMC ID: 7000217

PubMed ID: 31868165

SO-VID: b9c2a429-b06f-4ee8-9e50-89fef47220f1

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 12 July 2019

Date accepted : 20 December 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100004189, Max-Planck-Gesellschaft;

Award ID: Open-access funding

Award Recipient : Didier YR Stainier

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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Author impact statement 3D single cell imaging and genetic analyses reveal a new role of cardiac metabolism in cardiac wall morphogenesis.

ScienceOpen disciplines: Life sciences

Keywords: zebrafish,trabeculation,heart development,cardiomyocytes,metabolism,glycolysis

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: zebrafish, trabeculation, heart development, cardiomyocytes, metabolism, glycolysis

Metabolic modulation regulates cardiac wall morphogenesis in zebrafish

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Abstract

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Cancer Metabolism

Most cited references 40

Pyruvate kinase M2 is a phosphotyrosine-binding protein.

Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.

Genetics of congenital heart disease: the glass half empty.

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