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| Item Type: | Preprint |
|---|---|
| Title: | CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction |
| Creators Name: | Saadatmand, Alireza, Pepin, Mark, Chen, Zihao, Hartmann, Joshua, Sun, Qiang, Dewenter, Matthias, Nazir, Sumra, Paluvai, Harikrishnareddy, Hagenmüller, Marco, Haberkorn, Uwe, Schlicker, Lisa, Frias-Soler, Roberto Carlos, Tyedmers, Jens, Maack, Christoph, Schulze, Almut and Backs, Johannes |
| Abstract: | Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This “fuel switch” promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca(2+)/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [(18)F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and β-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2–NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.10.16.682731 |
| Date: | 16 October 2025 |
| Official Publication: | https://doi.org/10.1101/2025.10.16.682731 |
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