Background. Heart failure (HF) is driven by metabolic remodeling from fatty acid oxidation to glucose utilization which leads to alterations of glucose byproducts with subsequent posttranslational modifications of calcium handling proteins and thereby leads to systolic cardiac dysfunction (Lehmann et al. Nat Med 2018,24:62).

Results. In this study we investigate the role of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), a key regulator in pathological cardiac remodeling, for metabolic reprogramming in experimental cardiac dysfunction. We first confirmed that under pathological pressure overload, mice lacking CaMKIIδ and CaMKIIγ (double knockout; DKO) are protected from cardiac dysfunction as compared to control littermate (Ctrl). Strikingly, we then uncovered that metabolic remodeling, as exemplified by an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[¹⁸F] fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure in Ctrl. but not in DKO. RNAseq analysis revealed up-regulation of Nr4a1, a key transcription factor of glucose metabolism, which was coordinated with down-regulation of genes related to fatty acid utilization in Ctrl. after induced-pressure overload as compared to DKO. Steady-state analysis of metabolomic profiling from the same cardiac tissues revealed drastic depletion of lipid species in Ctrl.  upon pressure overload as compared to DKO. Interestingly, the same protective phenotype was observed in cardiac specific Nr4a1-KO mice compared to Ctrl. littermates under pathological pressure overload. Cardiac lipid staining showed more lipid reservoir in Nr4a1-KO mice compared to Ctrl. littermates. As proof-of-principles, adenoviral overexpression of Nr4a1 in iPSC-CM demonstrated reduction in fatty acids utilization.

Conclusion. Taken together, these findings implicate CaMKII-Nr4a1 as a regulatory axis of pathological cardiac metabolic reprogramming. A better understanding of this process may lead to new metabolic strategies for treating cardiomyopathies.