Exercise Training Mitigates Inhibition of Skeletal Muscle Mitochondrial Respiration with Empagliflozin Treatment in Male and Female Mice

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are antihyperglycemic drugs designed to lower renal glucose reabsorption, yet recent evidence indicates that SGLT2i have off-target effects on skeletal muscle to inhibit mitochondrial respiration. Such inhibition raises important questions regarding the interaction of SGLT2i and exercise on regulation of skeletal muscle mitochondrial metabolism. The purpose of the current study was to test the hypothesis that SGLT2i treatment (empagliflozin, EMPA) would blunt improvements to skeletal muscle mitochondrial oxidation capacity following aerobic training. Male and female C57BL/6J mice consumed a western diet (40% kcal from fat) for 8 weeks, then performed an additional 8 weeks of either treadmill training (5 times per week progressing up to 23 m/min) or remained sedentary. During the intervention period, all mice consumed either western diet or western diet enriched with EMPA (10mg/kg diet) in a 2x2 design (n=10/group for each sex). We isolated mitochondria from quadriceps muscles collected 72 hours after the final training session (or rest) and measured ex vivo mitochondrial substrate oxidation capacity using high-resolution respirometry. There was an interaction between exercise and EMPA (p=0.037) on complex I-II respiration whereby sedentary mice had lower respiration following EMPA versus untreated (-17% p=0.01) while exercise-trained mice had similar respiration between EMPA and untreated. The interaction was less prominent in complex I-supported respiration (p=0.06) or complex-II alone (p=0.09). Our results show that, contrary to expectations, EMPA treatment did not impair mitochondrial adaptations to exercise training. Instead, exercise training prevented the suppression of mitochondrial respiration during EMPA treatment. These findings indicate that aerobic exercise has positive effects on the off-target inhibition of mitochondrial respiration by SGLT2i. Supported by funding from the Collins Medical Trust (Wilsonville, Oregon) awarded to Matthew Robinson. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.