Cardiac-selective gene delivery of medium-chain acyl-CoA dehydrogenase (MCAD) does not protect against diabetes-induced cardiac dysfunction

Abstract

Abstract People with diabetes are at significantly higher risk of developing heart failure. Diabetic cardiomyopathy describes heart disease in patients with diabetes who have no other cardiac conditions. Specific therapies to treat the diabetic heart are limited. A key mechanism involved in the progression of diabetic cardiomyopathy is dysregulation of cardiac energy metabolism. The aim of this study was to determine if increasing the expression of medium chain acyl-coenzyme A dehydrogenase (MCAD; encoded by Acadm), a key regulator of fatty acid oxidation, could improve function of the diabetic heart. Male mice were administered streptozotocin to induce diabetes, which led to diastolic dysfunction 8 weeks post-injection. Mice then received cardiac-selective adeno-associated viral vectors encoding MCAD (rAAV6:MCAD) or control AAV and were followed for 8 weeks. rAAV6:MCAD did not improve diabetes-induced diastolic dysfunction or alter the expression of key metabolic genes (Ppargc1a, Ppara, Cpt1b, Slc2a4) or proteins (OXPHOS complexes). An inverse correlation between MCAD and perilipin 5 was observed, suggesting that altered MCAD expression may have an impact on lipid droplet accumulation in the diabetic heart.