Modelling metabolic shifts during cardiomyocyte differentiation, iron deficiency and transferrin rescue using human pluripotent stem cells

Johnson, Benjamin, Reinhold, Johannes, Holmes, Terri, Moore, Jamie A., Cowell, Verity, Bernardo, Andreia S., Rushworth, Stuart, Vassiliou, Vassilios ORCID: https://orcid.org/0000-0002-4005-7752 and Smith, James ORCID: https://orcid.org/0000-0003-0427-8678 (2022) Modelling metabolic shifts during cardiomyocyte differentiation, iron deficiency and transferrin rescue using human pluripotent stem cells. Metabolites, 12 (1). ISSN 2218-1989

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Abstract

Cardiomyocytes rely on specialised metabolism to meet the high energy demand of the heart. During heart development, metabolism matures and shifts from the predominant utilisation of glycolysis and glutamine oxidation towards lactate and fatty acid oxidation. Iron deficiency (ID) leads to cellular metabolism perturbations. However, the exact alterations in substrate metabolism during ID are poorly defined. Using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the present study investigated changes in major metabolic substrate utilisation in the context of ID or upon transferrin rescue. Typically, during hiPSC-CM differentiation, the greatest increase in total metabolic output and rate was seen in fatty acid metabolism. When ID was induced, hiPSC-CMs displayed increased reliance on glycolytic metabolism, and six TCA cycle, five amino acid, and four fatty acid substrates were significantly impaired. Transferrin rescue was able to improve TCA cycle substrate metabolism, but the amino acid and fatty acid metabolism remained perturbed. Replenishing iron stores partially reverses the adverse metabolic changes that occur during ID. Understanding the changes in metabolic substrate utilisation and their modification may provide potential for discovery of new biomarkers and therapeutic targets in cardiovascular diseases.

Item Type: Article
Additional Information: Funding Information: Funding: J.G.W.S. is supported by the Academy of Medical Sciences/the Wellcome Trust/the Government Department of Business, Energy and Industrial Strategy/the British Heart Foundation/Diabetes UK Springboard Award [SBF005\1057]. J.R. is supported by the National Institute of Health Research (NIHR).
Uncontrolled Keywords: cardiomyocytes,iron deficiency,pluripotent stem cells,molecular biology,biochemistry,endocrinology, diabetes and metabolism,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 23 Dec 2021 08:30
Last Modified: 15 Jul 2022 00:22
URI: https://ueaeprints.uea.ac.uk/id/eprint/82803
DOI: 10.3390/metabo12010009

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