Abstract 14278: Empagliflozin Restores Lowered Exercise Endurance Capacity via the Activation of Skeletal Muscle Fatty Acid Oxidation in Murine Heart Failure

Introduction:Exercise capacity, which is an independent predictor for poor prognosis, is attributed to markedly impaired skeletal muscle mitochondrial function along with fatty acid oxidation. Previous studies reported that administration of a sodium-glucose cotransporter 2 (SGLT2) inhibitor increases ketone body production and fat utilization in type 2 diabetic mice. We investigated the effects of SGLT2 inhibitor administration on the exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a heart failure (HF) murine model post-myocardial infarction (MI).Methods and Results:MI was created in male C57BL/6J mice by ligating the left coronary artery. A sham operation was performed in other mice. Two weeks post-MI, we divided the HF mice into two groups: treatment with or without the SGLT2 inhibitor, empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared to the sham and HF mice for 4 weeks after Empa administration. The exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice without affecting the cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weights. The mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle from the HF mice, and this decrease was ameliorated in the HF+Empa mice.Conclusions:Empagliflozin, an SGLT2 inhibitor, improved the exercise endurance and normalized the fatty acid oxidation in the skeletal muscle in post-infarct HF mice. Importantly, these beneficial effects of empagliflozin on exercise endurance were independent of glucose metabolism and cardiac function. SGLT2 inhibitors may be novel therapeutic agents against skeletal muscle dysfunction in HF.