CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Saadatmand, A.; Pepin, M. E.; Chen, Z.; Hartmann, J.; Sun, Q.; Dewenter, M.; Nazir, S.; Paluvai, H.; Hagenmueller, M.; Haberkorn, U.; Schlicker, L.; Frias-Soler, R. C.; Tyedmers, J.; Maack, C.; Schulze, A.; Backs, J.

doi:10.1101/2025.10.16.682731

bioRxiv · 10.1101/2025.10.16.682731

CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Saadatmand, A.·Pepin, M. E.·Chen, Z.·Hartmann, J.·Sun, Q.·Dewenter, M.·Nazir, S.·Paluvai, H.·Hagenmueller, M.·Haberkorn, U.·Schlicker, L.·Frias-Soler, R. C.·Tyedmers, J.·Maack, C.·Schulze, A.·Backs, J.

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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 Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]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 {beta}-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.

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Saadatmand, A., Pepin, M. E., Chen, Z., Hartmann, J., Sun, Q., Dewenter, M., Nazir, S., Paluvai, H., Hagenmueller, M., Haberkorn, U., Schlicker, L., Frias-Soler, R. C., Tyedmers, J., Maack, C., Schulze, A., Backs, J.. 2025-10-16. CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction. https://doi.org/10.1101/2025.10.16.682731

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