Cardiomyocyte-specific Fbxl5 deficiency promotes iron overload-driven hypercontractility and late-onset pathological...

Iron homeostasis in heart is essential for maintaining cardiac function, but its precise role in iron metabolism and its specific function remain incompletely understood.

We generated cardiomyocyte-specific Fbxl5 deficient mice (αMHC-Cre;Fbxl5^F/F). Those mice showed increased IRP2 protein levels, which in cardiomyocytes undergoes Fbxl5-dependent degradation. Young (12-week-old) αMHC-Cre;Fbxl5^F/F mice also showed upregulated levels of the IRP2, target transferrin receptor 1 (TfR1) and enhanced Fe³⁺ uptake into cardiomyocytes, increasing ferritin, total iron, and Fe²⁺ levels in cardiomyocytes. Fbxl5 deficiency increased both mitochondrial respiration capacity in isolated cardiac mitochondria and contractility of isolated cardiomyocytes, and in vivo, young αMHC-Cre;Fbxl5^F/F mice showed augmented cardiac contractility and improved exercise tolerance. By contrast, in aged (24-month-old) αMHC-Cre;Fbxl5^F/F mice, IRP2 levels were elevated relative to controls, but TfR1 upregulation and tissue iron accumulation were not seen. Accordingly, enhanced cardiac contractility and superior exercise tolerance phenotypes seen in young αMHC-Cre;Fbxl5^F/F mice were absent in comparably aged mice, which unexpectedly exhibited pathological cardiac hypertrophy and upregulation of heart failure-associated genes. Furthermore, we found that administration of sodium-glucose cotransporter-2 inhibitors (SGLT2i), whose cardioprotective effects have recently been suggested to involve enhanced myocardial iron storage, improved cardiac performance without altering myocardial iron content, suggesting that SGLT2i exerts cardioprotective effects largely independent of cardiac iron metabolism.

Cardiac iron dynamics are precisely regulated and tightly linked to cardiac function and prolonged dysregulation of iron dynamics can trigger cardiac pathological remodeling, even when iron balance is restored.