Sirtuin-3 is Essential for Glucagon-like Peptide-1-mediated Restoration of Diabetic Cardiomyopathy

Introduction: Sirtuin 3 (SIRT3) is a mitochondrial protein deacetylase and its expression is increased by fasting and exercise in skeletal muscle; however, the impact of anti-diabetic intervention on diabetic myocardium remained uncertain. Hypothesis: We hypothesized that the anti-diabetic remedy glucagon-like peptide-1 agonist (exendin-4; Ex4) may ameliorate mitochondrial remodeling observed in diabetic cardiomyopathy. Methods: Type 2 diabetic mice [T2DM; KKAy and dietary diabetes induced by high fat and high sucrose diet (HF/HS), male 14-16 w/o] and age- and gender-matched SIRT3 knockout mice with dietary diabetes (sirHF/HS) diet were allocated into Ex4 (24 nmole/kg/day for 40 days) and vehicle (CON) groups. Results: T2DM-CON and sirHF/HS-CON exhibited myocardial hypertrophy, increased fibrosis, decreased cardiac capillary density, and defragmented mitochondria, which were reversed by Ex4. Consistently with the changes in mitochondrial morphology, the mitochondrial regulatory proteins mitofusin-1 (Mfn1)...