Abstract Body: Metabolic inflexibility is an early driver of heart failure (HF), yet the upstream nutrient-sensing regulators remain poorly defined. Inositol Polyphosphate Multikinase (IPMK) integrates nutrient signals and regulates energy homeostasis in peripheral tissues, but its role in the heart is entirely unknown. We examined whether cardiomyocyte IPMK is required to maintain cardiac metabolic and structural integrity.
Cardiomyocyte-specific IPMK knockout (HKO) mice were generated by crossing ipmk-loxp mice with Myh6-Cre drivers. Longitudinal echocardiography was performed at 5, 10, and 15 weeks (n=8/group). Bulk RNA-sequencing was performed on left ventricular tissue across multiple time points (n=4/group). Enzymatic activities of pyruvate dehydrogenase (PDH) and citrate synthase (CS), acetyl-CoA, and NAD+/NADH ratios were quantified at 15 weeks. IPMK expression was also examined in publicly available human HF datasets.
IPMK mRNA was reduced ~20-25% in human HFpEF left ventricular tissue vs. healthy controls (p<0.05), with no change in HFrEF. HKO hearts were structurally normal at 5 weeks. By 10 weeks, fractional shortening (FS) was significantly reduced while ejection fraction (EF) remained preserved, with increased LV mass (p<0.005). By 15 weeks, both EF and FS declined significantly, with pronounced chamber dilation, interstitial fibrosis, and increased cardiomyocyte cross-sectional area (p<0.0005). Transcriptomic profiling revealed suppression of oxidative phosphorylation and TCA cycle pathways as early as 2 weeks, prior to detectable structural dysfunction. Biochemical analyses confirmed reduced PDH activity, CS activity, acetyl-CoA levels, and NAD+/NADH ratio in HKO hearts at 15 weeks (p<0.05), despite preserved mitochondrial content.
These findings identify IPMK as a novel cardiomyocyte-intrinsic regulator of mitochondrial metabolism. Loss of IPMK triggers early suppression of oxidative metabolism followed by progressive HF, establishing a new link between nutrient sensing and cardiac metabolic resilience.