Dapagliflozin alleviates mitochondrial damage in the myocardium under diabetic conditions by targeting sortilin

Abstract Background Type 2 diabetes patients are particularly vulnerable to myocardial injury, including mitochondrial damage in the myocardium. This study aims to evaluate the therapeutic potential and mechanisms of dapagliflozin in mitigating myocardial mitochondrial injury under diabetic conditions. Methods A cell model was established using a high-glucose, high-fat combination. Dapagliflozin was dissolved in Dimethyl sulfoxide (DMSO) and added to the culture medium. A type 2 diabetic mouse model was induced by high-fat feeding combined with Streptozotocin (STZ) injection, with dapagliflozin administered via oral gavage. SORT1 was silenced using siRNA. Phenotypic evaluation and mechanistic analysis were performed through qPCR, Western blot (WB), activity assays, Reactive Oxygen Species (ROS) measurement, transmission electron microscopy, and Masson’s staining. Results In vitro studies, we demonstrated that under diabetic conditions, mitochondrial damage was evident, characterized by a decrease in mitochondrial respiratory chain complex content, reduced complex activity, increased ROS levels, and structural damage to mitochondria. Silencing SORT1 resulted in a similar mitochondrial phenotype under diabetic conditions, highlighting the critical role of sortilin in mitochondrial function. Addition of dapagliflozin to the culture medium significantly improved mitochondrial dysfunction caused by high glucose and high fat, a finding also confirmed in the mouse model. Moreover, dapagliflozin alleviated myocardial fibrosis induced by diabetes in the mouse model. Conclusions Our findings uncover a novel molecular mechanism through which dapagliflozin improves myocardial mitochondrial injury under diabetic conditions, suggesting SORT1 as a potential therapeutic target for treating myocardial injury in diabetes.