Calcium/calmodulin-dependent kinases (CaMK) are members of the serine/threonine (Ser/Thr)-specific phosphokinase family that serve as critical regulators of cardiac energy metabolism and inflammatory responses. Chronic oxidative stress, characteristic of Heart Failure with preserved Ejection Fraction (HFpEF), leads to autonomous activation of CaMKII in the heart through oxidative modifications, subsequently causing adverse metabolic reprogramming and heart failure progression. HDAC4 is a principal target of CaMKII and plays a central role in response to elevated cardiac load. In human HDAC4, arginine at position 601 is critical for CaMKII binding and represents a unique docking site. Activated CaMKII binds and phosphorylates HDAC4 at S467 and S632, leading to its nuclear export via 14-3-3 protein binding. This disrupts the balance between protective class IIa and detrimental class I HDAC activities, promoting both hypertrophic gene expression and metabolic dysfunction. Unfortunately, the role of CaMKII-HDAC4 interaction in HFpEF remains incompletely understood, particularly regarding its effects on cardiac energy substrate utilisation. Recent studies demonstrate that HFpEF is characterised by a shift toward fatty acid oxidation as the predominant source of cardiac ATP production, with suppressed insulin-stimulated glucose oxidation. A two-hit approach for developing HFpEF was used to generate HFpEF in mutant HDAC4 knock-in mice (Hdac4R598F), equivalent to human HDAC4R601F, through the high-fat diet (HFD) and Nω-Nitro-L-arginine methyl ester (L-NAME). The Hdac4R598F mice, fed with HFD+L-NAME, gained less weight primarily due to lower fat mass, had better glucose tolerance, and were protected against hypertension and diastolic dysfunction. Protein expression analysis suggested that Hdac4R598F mice, fed with HFD+L-NAME, exhibited increased free fatty acid (FFA) uptake that was balanced by enhanced β-oxidation. In contrast, wild-type HFpEF mice exhibited increased FFA uptake but significantly reduced β-oxidation, resulting in lipotoxic accumulation. This metabolic imbalance in control mice mirrors clinical observations, where HFpEF patients demonstrate impaired metabolic flexibility and an excessive reliance on fatty acid oxidation, without adequate oxidative capacity. These findings suggest that the CaMKII-HDAC4 axis plays a central role in regulating lipid metabolism and mitochondrial physiology in the heart. Disruption of this pathway provides protection against the metabolic inflexibility characteristic of HFpEF. The preservation of balanced fatty acid uptake and oxidation in Hdac4R598F mice suggests that the CaMKII-HDAC4 axis normally constrains metabolic efficiency under pathological conditions. This work establishes the CaMKII-HDAC4 interaction as a promising target for pharmacological interventions to prevent maladaptive metabolic remodelling in patients with HFpEF, with potential therapeutic approaches including direct disruption of the CaMKII-HDAC4 protein-protein interaction.
