Deletion of Cardiac Fgf23 Impairs Myocardial Energy Metabolism and Ameliorates Fibrosis in a Pressure Overload Model in Mice

Left ventricular hypertrophy (LVH) is associated with increased cardiac expression of fibroblast growth factor (FGF23) in mice and men. To further elucidate the pathophysiological role of locally produced FGF23 in LVH, we specifically ablated Fgf23 in cardiomyocytes by crossing Fgf23 fl/fl mice with MLCv2-Cre transgenic mice, and employed transverse aortic constriction (TAC) to induce LVH by chronic pressure overload. The TAC-induced ~25-fold increase in cardiac Fgf23 mRNA expression was blunted in cardiomyocyte-specific Fgf23 knock-out ( Fgf23 CKO ) mice. Serum Fgf23 levels were equally increased in all genotypes after TAC, suggesting that cardiac-derived Fgf23 does not contribute to the TAC-induced rise in circulating Fgf23. Heart-to-body weight ratio, cardiomyocyte size, and molecular hypertrophy markers were similarly increased in all TAC groups, showing that LVH developed inde-pendently of cardiac Fgf23. However, Fgf23 CKO TAC mice showed reduced blood pressure upstream of the aortic constriction site, more pronounced eccentric hypertrophy, and a distinct reduction of cardiac fibrosis, relative to Fgf23 fl/fl TAC controls. Spatial metabolomics using mass spectrometry imaging in heart cryosections revealed that lack of local Fgf23 secretion reduced intracellular glucose abundance and impaired cardiac energy metabolism. Conversely, treatment of cultured cardiomyocytes with recombinant FGF23 stimulated the abundance of intracellular glucose as evidenced by mass spectrometry imaging. Collectively, our data uncover a novel function of cardiomyocyte-derived Fgf23 as modulator of energy metabolism and of cardiac fibrosis in LVH.