Gene and drug-mediated SERCA2a activation restores cardiac function and metabolic balance in diabetic mice

Diabetic cardiomyopathy is a major complication of diabetes mellitus, characterised by impaired calcium homeostasis, insulin resistance, and metabolic dysregulation. Notably, the expression and activity of sarco/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) are diminished in diabetic heart failure, contributing to both systolic and diastolic dysfunction. Although enhancing SERCA2a function has shown beneficial cardiac effects, the underlying metabolic mechanisms remain unclear. The objective of this study was to investigate the effect of pharmacological activation of SERCA2a in the diabetic heart. This study aimed to evaluate the impact of pharmacological activation of SERCA2a on cardiac function and metabolism in a diabetic context. Leptin-deficient (Ob/ob) diabetic mice were treated using two strategies: a novel SERCA2a allosteric agonist (CDN1163) and cardiac-specific overexpression via AAV9-mediated gene delivery. Both approaches attenuated the expression of genes involved in lipid synthesis and fatty acid oxidation, thereby improving lipid homeostasis. Enhanced SERCA2a activity promoted mitochondrial biogenesis, increased mitochondrial DNA content, improved oxidative phosphorylation, and elevated ATPase activity in diabetic hearts. In vitro , SERCA2a restoration in high glucose and H₂O₂-treated H9C2 myocytes normalised mitochondrial membrane potential and improved mitochondrial function. Additionally, SERCA2a activation mitigated lipotoxicity and cell injury through upregulation of antioxidant enzymes and suppression of ROS by inhibiting NADPH oxidase activity. Crucially, these molecular improvements translated into enhanced diastolic function in diabetic mice following both CDN1163 and AAV9-SERCA2a treatments. Collectively, our findings suggest SERCA2a activation may offer a promising therapy for diabetic cardiomyopathy by improving cardiac energetics, lipid metabolism, and mitochondrial function. • SERCA2a dysregulation disrupts calcium handling, contributing to heart failure, muscle dysfunction, and diabetes. • SERCA2a overexpression or activation by CDN1163 enhances ventricular function and mitigates cardiac dysfunction in Ob/ob mice. • These interventions enhance glucose and lipid metabolism, improve mitochondrial function, and reduce oxidative stress. • SERCA2a activation represents a promising therapeutic strategy for obesity-related cardiac dysfunction. • Targeting SERCA2a can enhance metabolic health and lessen complications linked to diabetes and obesity-related heart disease.