Abstract P310: Mitochondrial Electron Transport Chain Dysfunction Is Associated With Mg Deficiency Induced Diastolic Dysfunction

Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, although there is no specific treatment for HFpEF yet because of poor understanding of the underlying pathophysiology. Our previous studies show that hypomagnesemia contributes to diastolic dysfunction and HFpEF by regulation of mitochondrial function and that Mg supplementation improves diastolic function. In this study, we investigated how mitochondria were affected by Mg deficiency. Methods: C57BL/6J mice were fed with a low-Mg diet (HypoMg mice, 15-30 mg/kg Mg) or a normal Mg diet (control mice, 600 mg/kg Mg) for 6 weeks. Mg repletion was achieved by feeding HypoMg mice with normal diet for another 6 weeks. Results: HypoMg mice showed significantly decreased serum Mg (0.38±0.03 mM vs. 1.14±0.03 mM of control, P<0.0001), diastolic dysfunction (E/e’=21.1±1.1 vs. 15.4±0.4 of control, P=0.011), increased mitochondrial ROS (1.9±0.2-fold of control, P<0.0001), decreased total mitochondrial Mg content (3.6±1.8 vs. 18.3±4.7 μM total Mg/mg mitochondrial protein of control, P=0.019), decreased ATP production in hearts (1.2±0.2 vs. 2.7±0.2 μmol/g heart tissue of control, P=0.0002), decreased complex I activity (ΔOCR NADH-rotenone =0.27±0.10 vs. 1.02±0.04 of control, P=0.0004 measured with Seahorse), and decreased complex I protein levels (50.2% reduction compared with control mice, P=0.009). Mg repletion reversed all these changes. Conclusion: HypoMg-induced diastolic dysfunction likely results from HypoMg-induced electron transport chain dysfunction resulting from a decrease in mitochondrial Mg content. Mg repletion reverses these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms. In deficiency states, Mg supplementation may represent a novel treatment for diastolic heart failure by improving mitochondrial function.