Dataset Information

Cross-modal Integration of Metabolomics and Cardiac Functionality Captures Dynamic Metabotoxic Effects of Doxorubicin in Engineered Heart Tissues

ABSTRACT:

Here, we leveraged an innovative platform and a topology-guided integration framework to unveil the complex dose- and time-metabolic rewiring of the central carbon metabolism caused by doxorubicin-induced cardiotoxicity (DiC) in human heart tissue. Through cross-modal integration of cardiac functionality and metabolomics in 3D engineered heart tissues, we identified 20 metabolites linked to cardiac contraction and differentially affected by doxorubicin exposure. Nine of them, including carnitine esters and UDP-glucuronic acid, were never before implicated in DiC and represent promising candidates for DiC metabolic rescue.

By yielding high-resolution insights into complex biological mechanisms, our platform and mathematical framework enable metabolic and functional assessment of cardiotoxicity in functional heart models, paving the way for innovative advances in preclinical drug development.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase

PROVIDER: MTBLS13225 | MetaboLights | 2025-12-07

REPOSITORIES: MetaboLights

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Dataset's files

Source:

			Action	DRS
	a_MTBLS13225_LC-MS_negative_reverse-phase_metabolite_profiling-1.txt	Txt
	a_MTBLS13225_LC-MS_negative_reverse-phase_metabolite_profiling-2.txt	Txt
	a_MTBLS13225_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13225_LC-MS_negative_reverse-phase_metabolite_profiling-1_v2_maf.tsv	Tabular

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Publications

Cross-modal integration of metabolomics and cardiac functionality captures dynamic metabotoxic effects of doxorubicin in engineered heart tissues.

Conte Federica F Staykova Doroteya K DK Cofiño-Fabres Carla C Snippert Danique D van Rooij Arno A Lefeber Dirk J DJ Passier Robert R

Stem cell reports 20251204 1

Functional stem cell-derived heart models offer new avenues for preclinical, animal-free physiological assessment of drug cardiotoxicity. Yet, comprehensive molecular profiling in these models remains limited, leaving key metabolic drivers of cardiotoxicity unexplored. Here, we leveraged an innovative platform and a topology-guided integration framework to unveil the complex dose- and time-dependent metabolic rewiring of the central carbon metabolism caused by doxorubicin-induced cardiotoxicity ...[more]

PMID: 41349535

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Project description:Background: Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutic agents such as doxorubicin, and contributes to development of heart failure. There is a pressing need for cardiac-specific therapeutics that prevent the cardiac complications of chemotherapy without compromising efficacy by directly targeting cardiomyocyte loss. Objectives: We employed massively parallel combinatorial genetic screening to search for miRNA combinations that promote cardiomyocyte survival. Methods: Combinatorial genetics en masse (CombiGEM) screening in a cardiomyocyte cell line was followed by validation studies in the original cell type as well as primary cardiomyocytes to search for miRNA combinations that promote survival under various stress conditions. The top candidate combination was tested human iPSC-derived cardiomyocyte and in vivo mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing and in silico miRNA target prediction provided insight into possible mechanisms. Results: CombiGEM screens and validation experiments identified multiple miRNA combinations that protected cardiomyocytes from doxorubicin in vitro. The most effective miRNA combination (miR-222 + miR-455) appeared to act synergistically and had protective effects in both murine and zebrafish in vivo doxorubicin cardiotoxicity models. RNA sequencing data revealed synergistic and additive regulation of mechanistically relevant genes and biological processes, including mitochondrial homeostasis, cellular respiration, DNA replication/damage response, oxidative and ER stress, angiogenesis, muscle contraction/relaxation, and others. Conclusions: We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. The results of this study further our knowledge of the cardiac effects of individual miRNAs and their combinations and demonstrate the value of the CombiGEM approach for discovery of cardioprotective combinatorial therapeutic candidates.

Project description:To compare expression profiles in the cardiomyocytes with wild type top2b and those with top2b deletion after in vivo treatment of mice with doxorubicin or drug vehicle Doxorubicin is widely used in modern cancer treatments, despite the advent of targeted therapy. However, a dose-dependent cardiotoxicity often limits its clinical use. The prevailing theory hypothesizes that doxorubicin-induced cardiotoxicity is the result of reactive oxygen species (ROS) generation due to redox-cycling of doxorubicin. Here we showed that cardiomyocyte-specific deletion of Topoisomerase II beta (Top2b) markedly reduced DNA double-strand breaks, apoptosis, and functional damages in doxorubicin-treated hearts. To investigate transcriptomic changes after doxorubicin treatment in wild type mouse and mouse with cardiac specific deletion of Top2b, we examined the expression profiles in 4 groups of mice (3/group), ie. wildtype mice with or without doxorubicin treatment and mice with Top2b deletion in the cardiomyocytes with or without doxorubicin treatment. Mice were treated with doxorubicin (25mg/kg, i.p.) or PBS (drug vehicle) for 16 hr or 72 hr. The heart was removed and cardiomyocytes were isolated by using a Langendorff apparatus. After purification, total RNA was extracted from the cardiomyocytes, purified, and used for gene expression analysis. Compared with that in control cardiomyocytes or cardiomyocytes with Top2b deletion, doxorubicin caused a significant expression change in the genome of cardiomyocytes from the wildtype mice. Among the changes, multiple genes encoding mitochondrial structural protein and components of the respiratory chain complexes were down-regulated 72 hr after treatment while multiple genes in the p53 pathway were up-regulated 16 hr after treatment in the wildtype cardiomyocytes. Expression changes were examined in 2 groups of mice (wild type and conditional knockout of top2b in the cardiomyocytes) treated with doxorubicin or PBS for 16 or 72 hours