Acute Cardiac Ryanodine Receptor Loss-of-Function Leads to Cardiomyopathy and Metabolic Dysfunction: Implications for Diabetes Complications

Heart disease is a common complication of diabetes and is the leading cause of morbidity and mortality in patients. The cardiac ryanodine receptor Ca2+ channel (Ryr2) is reduced by up to 50% in several models of heart disease, including diabetic cardiomyopathy. However it is unclear which pathological characteristics of diabetic cardiomyopathy are caused by the loss of RYR2 protein in vivo. Thus, we tested whether an acute depletion of cardiac RYR2 protein is sufficient to recapitulate the reduced contractility, arrhythmias, cell death, and metabolic inflexibility associated with diabetic cardiomyopathy. Here, we report that conditional Ryr2 knockout mice (cRyr2KO) rapidly exhibit many of the functional, structural and molecular hallmarks of diabetic cardiomyopathy. Insulin receptor expression and cardioprotective pathways were reduced. Oxidative energy metabolism was blunted, and the flexibility of energy substrates was reduced. Consistent with a state of cellular energy starvation and stress, hypoxia-inducible factors were activated and uncoupling proteins were reduced to conserve energy. RYR2 controlled key/master transcriptional regulators of cardiomyocyte metabolism, differentiation, and survival, including Atf3, Klf15, and Sirt1/Foxo1/Pgc1α. Cell death was observed and associated with increased calpain-10 activation, but not caspase-3 activation or ER-stress. Our data show that loss of Ryr2 is sufficient to rapidly induce a complex phenotype reminiscent of diabetic cardiomyopathy and heart failure, placing RYR2 and its associated energy-stimulating Ca2+ fluxes upstream of both functional and metabolic pathologies. Together, our data allow us to predict that RYR2 loss-of-function in diabetic cardiomyopathy contributes to many aspects of the disease, making RYR2 stimulation a novel therapeutic target.