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

Benjamin Johnson, Johannes Reinhold, Terri Holmes, Jamie A. Moore, Verity Cowell, Andreia S. Bernardo, Stuart Rushworth, Vassilios Vassiliou, James Smith

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)
10 Downloads (Pure)

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.
Original languageEnglish
Article number9
JournalMetabolites
Volume12
Issue number1
Early online date22 Dec 2021
DOIs
Publication statusPublished - Jan 2022

Keywords

  • Cardiomyocytes
  • Iron deficiency
  • Pluripotent stem cells

Cite this