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

Area of Science:

• Cardiology
• Metabolic Research
• Biochemistry

Background:

• Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity impacts cardiac metabolism and function, with clinical trial relevance.
• SERCA influences glucose metabolism across tissues, but its cardiac role, especially in obesity-related hypertrophy, is under-explored.
• Pressure overload in obesity increases cardiac glucose oxidation; this study investigates SERCA's role in this context.

Purpose of the Study:

• To investigate the effects of SERCA activation on cardiac metabolism and function in obese mice.
• To test the hypothesis that SERCA activation increases ATP demand, promoting fat oxidation for energy homeostasis.

Main Methods:

• In vivo [U-13C3]lactate tracer experiments assessed cardiac metabolic fluxes in obese mice treated with CDN1163.
• Mathematical modeling of cardiac metabolism analyzed 13C enrichment in plasma and tissue metabolites.
• Echocardiography, gene expression, and enzymatic assays evaluated heart function and metabolism after 8 weeks of CDN1163.

Main Results:

• CDN1163 increased cardiac ATPase activity and decreased cytosolic Ca2+ signaling, glucose uptake, and glycolysis.
• Mitochondrial acetyl-CoA predominantly derived from non-glycolytic sources (e.g., fat), sustaining citric acid cycle flux and increasing mitochondrial activity.
• Gene expression of beta-oxidation and lipid handling enzymes was upregulated; no changes in basal cardiac function or remodeling were observed.

Conclusions:

• SERCA activation promotes the utilization of non-glucose substrates for cardiac mitochondrial metabolism in obese mice.
• This metabolic shift supports cardiac energy homeostasis by increasing fat oxidation.