Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies

Abstract

Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy.

Keywords: Bioenergetics; Cardiomyopathy; Human-induced pluripotent stem cells; Metabolism.

Graphical abstract

Figure 1

Schematic illustration of metabolic substrate preferences in cardiomyocytes under healthy vs. diseased conditions. Under healthy conditions, both fatty acids and glucose are able to enter the cell via the CD36 fatty acid translocase and GLUT4 transporter, respectively. Both substrates can enter the mitochondria and undergo OXPHOS; however, there is a preference for fatty acid β-oxidation as this process generates more ATP than glucose oxidation, which is critical for efficient energy production. In diabetic cardiomyopathy, GLUT4 membrane translocation is impaired, and as a result, glucose uptake is reduced. Increased fatty acid entry and β-oxidation then results in proton leak, ROS formation, and lipotoxicity, with eventual energy depletion. In dilated cardiomyopathy (DCM), an increase in glucose uptake and oxidation is accompanied by reduced fatty acid uptake and β-oxidation. Despite glucose being the more energy-efficient substrate, glucose oxidation is unable to produce sufficient energy to keep up with the demanding workload of a failing heart. In hypertrophic cardiomyopathy (HCM) and mitochondrial cardiomyopathy, much like in DCM, there is a metabolic switch towards preferential utilization of glucose. In HCM, however, an increase in glycolysis with concurrent reduction in glucose oxidation, results in uncoupling between glucose entry and oxidation. This leads to suboptimal OXPHOS and insufficient energy production. In anthracycline cardiomyopathy and peripartum cardiomyopathy, fatty acid and glucose cellular uptake and oxidation have yet to be elucidated. While ROS formation has been identified as a common occurrence, disrupted mitochondrial structure has been observed in anthracycline cardiomyopathy. Both cardiomyopathies are associated with impaired OXPHOS, leading to insufficient energy production.

Figure 2

Schematic illustration summarizing the advantages and disadvantages of hiPSCs and animal models in terms of identifying novel targets and personalized therapies.