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Fig. 1 | Stem Cell Research & Therapy

Fig. 1

From: Characterization of cardiac metabolism in iPSC-derived cardiomyocytes: lessons from maturation and disease modeling

Fig. 1

The adult cardiomyocytes versus immature iPSC-CMs and matured iPSC-CMs. Comparison of the structure and metabolism of adult cardiomyocytes (A, B), immature iPSC-CMs (C, D) and matured iPSC-CMs (E, F). A Adult cardiomyocytes are elongated, with sarcomeres organized in myofibrils. Mitochondria are aligned with the myofibrils in the horizontal direction of the cardiomyocyte. L-type Ca2+ channels are present on the membrane and in the T-tubules, in close proximity to the RyRs to ensure fast calcium signal transduction. Calcium can be extruded via the NCX. B Schematic overview of substrate use in the adult cardiomyocyte. Fatty acids enter from the blood via the FAT/CD36 in the cardiomyocyte. After conversion to acyl-CoA, transport into the mitochondria takes place via CPT1 and CPT2 to enter the matrix. Fatty-acyl-CoA enter FAO to yield acetyl CoA, which can enter the TCA cycle. Glucose enters from the blood via the GLUT4, or is derived from glycogen storage in the cardiomyocyte. Glucose enters glycolysis to yield either lactate or pyruvate, which can then cross the mitochondrial membrane. The end product acetyl CoA can enter the TCA cycle. The by-products of the TCA cycle, NADH and FADH2 deliver electrons to the ETC to power ATP production at the ATP synthase. C iPSC cardiomyocytes are smaller and rounder compared to adult cardiomyocytes, with a single nucleus. Sarcomeres are organized, but not well aligned. L-type Ca2+ channels are present, but not in close proximity to RyR. Mitochondria are round with less cristae and are more often perinuclear than peri-sarcomeric. D Immature iPSC-CMs demonstrate the main processes in cardiac metabolism. However, iPSC-CMs mainly rely on glycolysis in contrast to FAO for energy production. E Matured iPSC-CMs become more elongated, with binucleation, aligned sarcomeres, higher SR maturity (more RyRs) and more mitochondria. F Mitochondria increase in mass and change from surrounding the nucleus to surrounding the sarcomeres. Glucose uptake decreases in the matured iPSC-CMs, as well as overall glycolysis, lactate production and glucose consumption (not depicted). Glucose oxidation, glycolytic capacity and glycolytic reserve increase and FAO and oxidative phosphorylation become more pronounced in matured iPSC-CMs. Mitochondrial DNA increases and mitochondrial membrane potential becomes higher. To emphasize the changes that occur during maturation in the iPSC-CMs, only the glucose transporter, and not other substrate transporters, was depicted in D, F. For the same reason, the presence of mitochondrial DNA was omitted on purpose in B. BCAA branched chain amino acids; Ca2+ calcium; CPT1/2 carnitine palmitoyltransferase I/II; Cx43 connexin 43; ETC electron transport chain; FAO fatty acid oxidation; FAT/CD36 fatty acid translocase/cluster of differentiation 36; GLUT4 glucose transporter type 4; iPSC-CMs induced pluripotent stem cell-derived cardiomyocytes; NCX sodium–calcium exchanger; OXPHOS oxidative phosphorylation; RyR ryanodine receptor; SERCA sarco/endoplasmic reticulum Ca2+ ATPase; SR sarcoplasmic reticulum; TCA cycle tricarboxylic acid cycle; T-tubule transverse tubules

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