PKP2 orchestrates OXPHOS expression in cardiomyocytes via a PGC1α-dependent mechanism
Han, S. J.; den Berg, D.; de Ruiter, H.; Tsui, H.; Kyriakopoulou, E.; Koopmans, T.; Perini, I.; Monshouwer-Kloots, J.; van Kampen, S. J.; te Riele, A. S. J. M.; Kelters, I. R.; Gianoli, M.; Burgering, B. M. T.; van Rooij, E.
Show abstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease where the majority of ACM patients carry a (likely) pathogenic variant in desmosomal genes, predominantly in plakophilin-2 (PKP2). While the genetic cause of the disease is well studied, the molecular disease-driving mechanisms and how exercise can drive disease progression remain poorly understood. In this study, we identified the oxidative phosphorylation (OXPHOS) pathway to be downregulated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and human explanted hearts carrying pathogenic PKP2 variants. The reduced expression of OXPHOS related genes was a result of lower PPARGC1A expression which led to decreased mitochondrial spare capacity in PKP2 mutant hiPSC-CMs. Induction of PPARGC1A expression partially restored the expression of OXPHOS components and improved contractility in PKP2 mutant cells. These results suggest that improving oxidative capacity through modulation of PPARGC1A in cardiomyocytes could be considered as a new therapeutic target for ACM patients in the future.
Matching journals
The top 11 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Human Erbb2-induced Erk Activity Robustly Stimulates Cycling and Functional Remodeling of Rat and Human Cardiomyocytes 96%
- Human induced pluripotent stem cell-derived cardiomyocytes to study inflammation-induced diastolic dysfunction 95%
- AARS2 ameliorates myocardial ischemia via fine-tuning PKM2-mediated metabolism 95%
Similar papers in this journal
- dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function 95%
- Isolated Mouse Adult Cardiomyocytes Display Minimal Mitochondrial ATP Demand and Maximal Reliance on Glycolysis 95%
- Viral expression of a SERCA2a-activating PLB mutant improves calcium cycling and synchronicity in dilated cardiomyopathic hiPSC-CMs 94%
Similar papers in this journal
- Modeling cardiac fibroblast heterogeneity from human pluripotent stem cell-derived epicardial cells 95%
- A microRNA program controls the transition of cardiomyocyte hyperplasia to hypertrophy and stimulates mammalian cardiac regeneration 95%
- Cardiomyocyte Contractile Impairment in Heart Failure Results from Reduced BAG3-mediated Sarcomeric Protein Turnover 94%
Similar papers in this journal
- Isogenic sets of hiPSC-CMs harboring KCNH2 mutations capture location-related phenotypic differences 96%
- Human iPSC-Based Model Reveals NOX4 as Therapeutic Target in Duchenne Cardiomyopathy 96%
- A simplified co-culture reveals altered cardiotoxic responses to doxorubicin in hPSC-derived cardiomyocytes in the presence of endothelial cells 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.