TY - JOUR
T1 - Modelling metabolic shifts during cardiomyocyte differentiation, iron deficiency and transferrin rescue using human pluripotent stem cells
AU - Johnson, Benjamin
AU - Reinhold, Johannes
AU - Holmes, Terri
AU - Moore, Jamie A.
AU - Cowell, Verity
AU - Bernardo, Andreia S.
AU - Rushworth, Stuart
AU - Vassiliou, Vassilios
AU - Smith, James
N1 - 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).
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - Cardiomyocytes
KW - Iron deficiency
KW - Pluripotent stem cells
UR - http://www.scopus.com/inward/record.url?scp=85121673899&partnerID=8YFLogxK
U2 - 10.3390/metabo12010009
DO - 10.3390/metabo12010009
M3 - Article
VL - 12
JO - Metabolites
JF - Metabolites
SN - 2218-1989
IS - 1
M1 - 9
ER -
