Dataset Information

Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency

ABSTRACT: Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERRα loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers.

INSTRUMENT(S): Q Exactive

SUBMITTER: Catherine R. Dufour

PROVIDER: MTBLS795 | MetaboLights | 2022-09-20

REPOSITORIES: MetaboLights

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			Action	DRS
	MTBLS795	Other
	FILES	Other
	a_MTBLS795_Method1_POS_1_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS795_Method2_POS_2_metabolite_profiling_mass_spectrometry.txt	Txt
	a_MTBLS795_Method3_NEG_1_metabolite_profiling_mass_spectrometry.txt	Txt

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Integrated multi-omics analysis of adverse cardiac remodeling and metabolic inflexibility upon ErbB2 and ERRα deficiency.

Dufour Catherine R CR Xia Hui H B'chir Wafa W Perry Marie-Claude MC Kuzmanov Uros U Gainullina Anastasiia A Dejgaard Kurt K Scholtes Charlotte C Ouellet Carlo C Zuo Dongmei D Sanguin-Gendreau Virginie V Guluzian Christina C Smith Harvey W HW Muller William J WJ Audet-Walsh Etienne E Sergushichev Alexey A AA Emili Andrew A Giguère Vincent V

Communications biology 20220912 1

Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 ...[more]

PMID: 36097051

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Project description:Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. We performed a comprehensive multi-omics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in the creatine kinase and ATP synthesis. Accompanying these metabolic derangements, quantitative electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase (CS) activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species (ROS) and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.