Repression of Osmr and Fgfr1 by miR-1/133a prevents cardiomyocyte dedifferentiation and cell cycle entry in the adult heart

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Abstract

The muscle-specific miR-1 and miR-133a RNAs lock cardiomyocytes in a differentiated state by suppressing OSMR/FGFR signaling.

Abstract

Dedifferentiation of cardiomyocytes is part of the survival program in the remodeling myocardium and may be essential for enabling cardiomyocyte proliferation. In addition to transcriptional processes, non-coding RNAs play important functions for the control of cell cycle regulation in cardiomyocytes and cardiac regeneration. Here, we demonstrate that suppression of FGFR1 and OSMR by miR-1/133a is instrumental to prevent cardiomyocyte dedifferentiation and cell cycle entry in the adult heart. Concomitant inactivation of both miR-1/133a clusters in adult cardiomyocytes activates expression of cell cycle regulators, induces a switch from fatty acid to glycolytic metabolism, and changes expression of extracellular matrix genes. Inhibition of FGFR and OSMR pathways prevents most effects of miR-1/133a inactivation. Short-term miR-1/133a depletion protects cardiomyocytes against ischemia, while extended loss of miR-1/133a causes heart failure. Our results demonstrate a crucial role of miR-1/133a–mediated suppression of Osmr and Ffgfr1 in maintaining the postmitotic differentiated state of cardiomyocytes.

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Most cited references 77

Record: found
Abstract: found
Article: not found

Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles

A. Subramanian, P. Tamayo, V. K. Mootha … (2005)

Although genomewide RNA expression analysis has become a routine tool in biomedical research, extracting biological insight from such information remains a major challenge. Here, we describe a powerful analytical method called Gene Set Enrichment Analysis (GSEA) for interpreting gene expression data. The method derives its power by focusing on gene sets, that is, groups of genes that share common biological function, chromosomal location, or regulation. We demonstrate how GSEA yields insights into several cancer-related data sets, including leukemia and lung cancer. Notably, where single-gene analysis finds little similarity between two independent studies of patient survival in lung cancer, GSEA reveals many biological pathways in common. The GSEA method is embodied in a freely available software package, together with an initial database of 1,325 biologically defined gene sets.

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Record: found
Abstract: found
Article: not found

PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.

Vamsi K Mootha, Cecilia M. Lindgren, Karl-Fredrik Eriksson … (2003)

DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.

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Article: not found

The Fibroblast Growth Factor signaling pathway

David M. Ornitz, Nobuyuki Itoh (2015)

The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. © 2015 Wiley Periodicals, Inc.

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Author and article information

Contributors

Melissa Valussi:

ORCID: https://orcid.org/0000-0001-8079-4776

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Johannes Besser: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - original draft

Katharina Wystub-Lis: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Sven Zukunft:

ORCID: https://orcid.org/0000-0002-1811-4562

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SupervisionRole: Validation

Manfred Richter:

ORCID: https://orcid.org/0000-0002-6239-3503

Role: Resources

Thomas Kubin: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ResourcesRole: VisualizationRole: Writing - review & editing

Thomas Boettger:

ORCID: https://orcid.org/0000-0003-4280-8449

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Thomas Braun:

ORCID: https://orcid.org/0000-0002-6165-4804

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: October 2021

Publication date (Electronic, pub): 13 October 2021

Volume: 7

Issue: 42

Electronic Location Identifier: eabi6648

Affiliations

[1 ]Department of Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, Ludwigstrasse 43, D-61231 Bad Nauheim, Germany.

[2 ]Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, D-60590 Frankfurt am Main, Germany.

[3 ]Department of Cardiac Surgery, Kerckhoff Heart Center, Benekestrasse 2-8, D-61231 Bad Nauheim, Germany.

[4 ]German Center for Cardiovascular Research (DZHK), Berlin, Germany.

[5 ]German Center for Lung Research (DZL), Giessen, Germany.

Author notes

[* ]Corresponding author. Email: thomas.boettger@ 123456mpi-bn.mpg.de (T.Bo.); thomas.braun@ 123456mpi-bn.mpg.de (T.Br.)

Author information

Melissa Valussi https://orcid.org/0000-0001-8079-4776

Sven Zukunft https://orcid.org/0000-0002-1811-4562

Manfred Richter https://orcid.org/0000-0002-6239-3503

Thomas Boettger https://orcid.org/0000-0003-4280-8449

Thomas Braun https://orcid.org/0000-0002-6165-4804

Article

Publisher ID: abi6648

DOI: 10.1126/sciadv.abi6648

PMC ID: 8514096

PubMed ID: 34644107

SO-VID: 1d332a2f-249d-48c3-9b4c-860379ccc283

Copyright © Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 23 March 2021

Date accepted : 19 August 2021

Funding

Funded by: doi http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: 267 TP A05

Funded by: doi http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: RTG2355

Funded by: doi http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: 1213 TP B02

Funded by: doi http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Award ID: 81 TP A02

Funded by: doi http://dx.doi.org/10.13039/100005930, ASCRS Research Foundation;

Funded by: doi http://dx.doi.org/10.13039/100010447, Deutsches Zentrum far Herz-Kreislaufforschung;

Award ID: 81Z0200302

Funded by: doi http://dx.doi.org/10.13039/100010447, Deutsches Zentrum far Herz-Kreislaufforschung;

Funded by: doi http://dx.doi.org/10.13039/501100013430, China Power Investment Corporation;

Award ID: EXC2026

Funded by: doi http://dx.doi.org/10.13039/501100013430, China Power Investment Corporation;

Award ID: 390649896