Molecular Atlas of Postnatal Mouse Heart Development

Virpi Talman, Jaakko Sakari Teppo, Päivi Anneli Pöhö, Parisa Movahedi, Anu Vaikkinen, Suvi Tuuli Karhu, Kajetan Trošt, Tommi Suvitaival, Jukka Heikkonen, Tapio Pahikkala, Ahti Antti Tapio Kotiaho, Risto Kalervo Kostiainen, Markku Tapio Varjosalo, Heikki Juhani Ruskoaho

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Background

The molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA, protein, and metabolite changes in the neonatal heart for identification of metabolism‐related mechanisms associated with cardiac regeneration.
Methods and Results

Methods and results

Mouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c‐means clustering were used to identify up‐ or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNAs and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS (HMG‐CoA [hydroxymethylglutaryl‐coenzyme A] synthase)–mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU‐positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle.

Conclusions

This study is the first systems‐level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies
Original languageEnglish
Article number010378
JournalJournal of the American Heart Association
Volume7
Issue number20
Number of pages46
ISSN2047-9980
DOIs
Publication statusPublished - 16 Oct 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • heart development
  • heart regeneration
  • metabolomics
  • neonatalmouse cardiomyocyte
  • proteomics
  • transcriptomics
  • MYOCARDIAL-INFARCTION
  • CARDIOMYOCYTE PROLIFERATION
  • MEVALONATE PATHWAY
  • GENE-EXPRESSION
  • REGENERATION
  • METABOLISM
  • PROTEIN
  • REPAIR
  • YOUNG
  • DEDIFFERENTIATION
  • 116 Chemical sciences
  • 317 Pharmacy

Cite this

@article{bedfdcc67e4c4059bb4c1decc6238bcc,
title = "Molecular Atlas of Postnatal Mouse Heart Development",
abstract = "BackgroundThe molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA, protein, and metabolite changes in the neonatal heart for identification of metabolism‐related mechanisms associated with cardiac regeneration.Methods and ResultsMethods and resultsMouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c‐means clustering were used to identify up‐ or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNAs and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS (HMG‐CoA [hydroxymethylglutaryl‐coenzyme A] synthase)–mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU‐positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle.ConclusionsThis study is the first systems‐level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies",
keywords = "heart development, heart regeneration, metabolomics, neonatalmouse cardiomyocyte, proteomics, transcriptomics, MYOCARDIAL-INFARCTION, CARDIOMYOCYTE PROLIFERATION, MEVALONATE PATHWAY, GENE-EXPRESSION, REGENERATION, METABOLISM, PROTEIN, REPAIR, YOUNG, DEDIFFERENTIATION, 116 Chemical sciences, 317 Pharmacy",
author = "Virpi Talman and Teppo, {Jaakko Sakari} and P{\"o}h{\"o}, {P{\"a}ivi Anneli} and Parisa Movahedi and Anu Vaikkinen and Karhu, {Suvi Tuuli} and Kajetan Trošt and Tommi Suvitaival and Jukka Heikkonen and Tapio Pahikkala and Kotiaho, {Ahti Antti Tapio} and Kostiainen, {Risto Kalervo} and Varjosalo, {Markku Tapio} and Ruskoaho, {Heikki Juhani}",
year = "2018",
month = "10",
day = "16",
doi = "10.1161/JAHA.118.010378",
language = "English",
volume = "7",
journal = "Journal of the American Heart Association",
issn = "2047-9980",
publisher = "Wiley",
number = "20",

}

Molecular Atlas of Postnatal Mouse Heart Development. / Talman, Virpi; Teppo, Jaakko Sakari; Pöhö, Päivi Anneli; Movahedi, Parisa; Vaikkinen, Anu; Karhu, Suvi Tuuli; Trošt, Kajetan; Suvitaival, Tommi; Heikkonen, Jukka; Pahikkala, Tapio; Kotiaho, Ahti Antti Tapio; Kostiainen, Risto Kalervo; Varjosalo, Markku Tapio; Ruskoaho, Heikki Juhani.

In: Journal of the American Heart Association, Vol. 7, No. 20, 010378, 16.10.2018.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Molecular Atlas of Postnatal Mouse Heart Development

AU - Talman, Virpi

AU - Teppo, Jaakko Sakari

AU - Pöhö, Päivi Anneli

AU - Movahedi, Parisa

AU - Vaikkinen, Anu

AU - Karhu, Suvi Tuuli

AU - Trošt, Kajetan

AU - Suvitaival, Tommi

AU - Heikkonen, Jukka

AU - Pahikkala, Tapio

AU - Kotiaho, Ahti Antti Tapio

AU - Kostiainen, Risto Kalervo

AU - Varjosalo, Markku Tapio

AU - Ruskoaho, Heikki Juhani

PY - 2018/10/16

Y1 - 2018/10/16

N2 - BackgroundThe molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA, protein, and metabolite changes in the neonatal heart for identification of metabolism‐related mechanisms associated with cardiac regeneration.Methods and ResultsMethods and resultsMouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c‐means clustering were used to identify up‐ or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNAs and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS (HMG‐CoA [hydroxymethylglutaryl‐coenzyme A] synthase)–mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU‐positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle.ConclusionsThis study is the first systems‐level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies

AB - BackgroundThe molecular mechanisms mediating postnatal loss of cardiac regeneration in mammals are not fully understood. We aimed to provide an integrated resource of mRNA, protein, and metabolite changes in the neonatal heart for identification of metabolism‐related mechanisms associated with cardiac regeneration.Methods and ResultsMethods and resultsMouse ventricular tissue samples taken on postnatal day 1 (P01), P04, P09, and P23 were analyzed with RNA sequencing and global proteomics and metabolomics. Gene ontology analysis, KEGG pathway analysis, and fuzzy c‐means clustering were used to identify up‐ or downregulated biological processes and metabolic pathways on all 3 levels, and Ingenuity pathway analysis (Qiagen) was used to identify upstream regulators. Differential expression was observed for 8547 mRNAs and for 1199 of 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Differentially regulated metabolic pathways include branched chain amino acid degradation (upregulated at P23), fatty acid metabolism (upregulated at P04 and P09; downregulated at P23) as well as the HMGCS (HMG‐CoA [hydroxymethylglutaryl‐coenzyme A] synthase)–mediated mevalonate pathway and ketogenesis (transiently activated). Pharmacological inhibition of HMGCS in primary neonatal cardiomyocytes reduced the percentage of BrdU‐positive cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating the cardiomyocyte cell cycle.ConclusionsThis study is the first systems‐level resource combining data from genomewide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses in the mouse heart throughout the early postnatal period. These integrated data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies

KW - heart development

KW - heart regeneration

KW - metabolomics

KW - neonatalmouse cardiomyocyte

KW - proteomics

KW - transcriptomics

KW - MYOCARDIAL-INFARCTION

KW - CARDIOMYOCYTE PROLIFERATION

KW - MEVALONATE PATHWAY

KW - GENE-EXPRESSION

KW - REGENERATION

KW - METABOLISM

KW - PROTEIN

KW - REPAIR

KW - YOUNG

KW - DEDIFFERENTIATION

KW - 116 Chemical sciences

KW - 317 Pharmacy

U2 - 10.1161/JAHA.118.010378

DO - 10.1161/JAHA.118.010378

M3 - Article

VL - 7

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

SN - 2047-9980

IS - 20

M1 - 010378

ER -