Abstract

Introduction: Hypomagnesemia (HypoMg) and subsequent oxidative stress cause diabetic cardiac diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF). A Mg 2+ transporter with both channel and kinase function, the transient receptor potential cation channel subfamily M 7 (TRPM7), is upregulated in HypoMg. Inhibition of TRPM7 kinase prevents HypoMg-mediated oxidative stress in the brain. Aims: We investigated the role of TRPM7 kinase in cardiomyocyte mitochondrial regulation and DD. Methods: Wild type (WT) C57BL/6J mice and transgenic mice with a global K1646R mutation in the TRPM7 kinase domain, TRPM7 K1646R (without kinase function) were fed with either a normal diet (control, 2000 mg/kg Mg 2+ ), high fat diet (HFD, 60% kcal from fat), or a low Mg 2+ diet (HypoMg, 15-30 mg/kg Mg 2+ ) starting from 10 weeks old. HFD lasted for 23-25 weeks. HypoMg diet lasted for 6 weeks. Mouse ventricles, cardiomyocytes, and mitochondria and human cardiac cell line, RL-14, were used for analysis. Results: Diabetic mice on HFD had HypoMg and elevated TRPM7 protein levels in heart. DM-associated DD was prevented by TRPM7 K1646R . In HypoMg mouse ventricles, TRPM7 mRNA and protein levels were also increased. HypoMg-induced DD (increased E/e’, decreased resting sarcomere length, and increased S-glutathionylated cardiac myosin binding protein C) and mitochondrial dysfunction (increased mitoROS, depolarized mitochondrial membrane potential, and decreased ATP, mitochondrial Mg 2+ and complex I/II activities) were prevented by TRPM7 K1646R . TRPM7 kinase regulated the overexpression of a Src kinase family member Fgr in mitochondria of HypoMg mouse ventricles, which co-localized with complex II, regulated complex II activity, and led to increased mitoROS. Conclusion: TRPM7 mediated mitochondrial dysfunction and cardiac DD in HypoMg. TRPM7 kinase enhanced Fgr expression in mitochondria, with subsequent complex II dysfunction and mitoROS overproduction. Inhibition of TRPM7 kinase function represents a potential novel therapeutic strategy to treat diabetic HFpEF.