Sarco/Endoplasmic Reticulum Ca²⁺ ATPase Activation Shifts Cardiac Fuel Preference Without Impairing Cardiac Function...

Activity of SERCA (sarco/endoplasmic reticulum Ca²⁺ ATPase) affects cardiac metabolism and function and is under investigation in clinical trials. SERCA function also regulates glucose metabolism in multiple tissues, but it is unknown how these effects extend to the heart. Pressure overload-induced cardiac hypertrophy corresponds to increased cardiac glucose oxidation in obesity. We hypothesized that SERCA activation by the compound CDN1163 would increase ATP demand due to Ca²⁺ cycling, leading to increased fat oxidation to maintain cardiac energy homeostasis.

In vivo [U-¹³C₃]lactate tracer experiments were performed to assess fasting cardiac metabolic fluxes in Mc4r^-/- mice fed a Western diet and treated with CDN1163. Fluxes were estimated by fitting a mathematical model of cardiac metabolism to ¹³C enrichment measurements of plasma and tissue metabolites taken at the end of the isotope infusion. Metabolic flux measurements were combined with echocardiography, gene expression, and enzymatic assays to assess the effects of SERCA activation on heart function and metabolism following 8 weeks of CDN1163 treatment.

CDN1163 increased cardiac ATPase activity, decreased cytosolic Ca²⁺ signaling, and decreased cardiac glucose uptake and glycolysis in obese mice. A greater fraction of mitochondrial acetyl-coenzyme A was obtained from nonglycolytic sources, such as fat, to sustain citric acid cycle flux, corresponding to an increase in mitochondrial activity. CDN1163 treatment upregulated gene expression of enzymes in β-oxidation and lipid handling. No changes in basal cardiac function or compensatory left ventricular remodeling were observed.

SERCA activation promotes flux from nonglucose substrates to fuel cardiac mitochondrial metabolism in obese mice.