| Autor: |
Magdalena Harakalova, Jiayi Pei, Renee Maas, Karen Gaar-Humphreys, Johannes Gho, Emilia Nagyova, Christian Snijders Blok, Iris van Adrichem, René van Es, Shahrzad Sepehrkhouy, Dries Feyen, Noortje van den Dungen, Nico Lansu, Jorg Calis, Niels van der Kaaij, Nicolaas de Jonge, Linda van Laake, Anneline ter Riele, Manon Huibers, Roel de Weger, Marianne C. Verhaar, J. Peter van Tintelen, Frederic Vaz, Boudewijn Burgering, Alain van Mil, Jan Buikema, Aryan Vink, Ioannis Karakikes, Mark Mercola, Pieter AFM Doevendans, Joost Sluijter, Frank van Steenbeek, Caroline Cheng, Michal Mokry, Folkert Asselbergs |
| Rok vydání: |
2022 |
| Popis: |
Carriers of the R14del pathogenic variant in the phospholamban (PLN) gene develop severe cardiomyopathy with extracellular adipocyte infiltration and intracellular cardiomyocyte mitochondrial disturbances. However, the basis of this metabolic dysregulation tailoring potential treatment targets is unknown. Here, we present a combined approach of transcriptional regulation analysis in human primary tissue and validation in a unique long-term (160 days) matured human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. We demonstrate a dysregulated PPARA-mediated mitochondrial fatty acid oxidation (FAO) signalling in PLN-R14del hearts and hiPSC-CMs. PLN-R14del hiPSC-CMs also displayed a higher preference for glycolysis over FAO and presented limited flexibility in energy substrate switching leading to enhanced lipid droplet storage. By activating PPARA in PLN-R14del hiPSC-CMs using bezafibrate, we observed an improved mitochondrial structure and calcium handling function, further indicating the importance of FAO in the disease and the potential of PPARA agonists as a novel therapeutic strategy in cardiomyopathies. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
