Molecular Atlas of Postnatal Mouse Heart Development

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 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 mRNA s 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.

Cross-Sectional Transcriptional Analysis of the Aging Murine Heart

“…This research supports ongoing efforts to characterize the transcriptional signatures of aging and development. Recent similar works have attempted to characterize differential gene expression in the fetal human heart (Pervolaraki et al, 2018), the neonatal mouse heart (Talman et al, 2018), and the elderly mouse heart (Bartling et al, 2019) but none have investigated gene expression across the entirety of the mouse lifespan. The whole-lifespan view provides greater resolution than the two group comparisons (old vs. young) traditionally used in agerelated gene expression studies (Bodyak et al, 2002;Lee et al, 2002;Bartling et al, 2019).…”

Three in a Box: Understanding Cardiomyocyte, Fibroblast, and Innate Immune Cell Interactions to Orchestrate Cardiac Repair Processes

“…Moreover, cardiac regeneration and proliferation of cardiomyocytes may be regulated by their metabolic and oxidative status and hypoxia (57–59), as well as genes involved in mitochondrial quality control (60). Importantly, extrinsic cues such as physical interactions with extracellular space and matrix (61, 62) and even the innervation of the cardiac tissue (63) are crucial determinants.…”

Silencing of Sphingosine kinase 1 Affects Maturation Pathways in Mouse Neonatal Cardiomyocytes

“…Our results demonstrate that Sphk1 silencing may favor the neonatal to adult CM transition. Transcriptomic and subsequent pathway analysis of Sphk1 -lacking AngII-treated CMs revealed a marked upregulation of cardiac developmental pathways, as well as downregulation of pathways related to cell proliferation, which is characteristic of maturing CMs [ 27 ]. Additionally, Sphk1 silencing altered pathways related to CM contractility, metabolism/mitochondrial function and endocytosis in a similar direction as that observed in maturing murine CMs postnatally in the study by Giudice et al [ 20 ].…”