Exercise and sodium-glucose cotransporter-2 inhibitor therapy independently affect mitochondrial quality control in the liver

Mitochondrial dysfunction is associated with conditions like type 2 diabetes (T2D). Mitochondrial fission, fusion, and mitophagy are mechanisms by which mitochondrial quality can be regulated and alleviate mitochondrial dysfunction. Both exercise training (EX) and sodium glucose cotransporter-2 inhibitors (SGLT2i) are therapies that improve T2D and its associated metabolic dysfunction. However, it is not understood how SGLT2i therapy influences regulators of mitochondrial quality either independently or in combination with EX in the liver. Objective: To assess the effects of SGLT2i therapy, EX, and the combination on mitochondrial quality control-related proteins in the liver in a rat model of glucose intolerance. HYPOTHESIS: SGLT2i therapy, EX, and their combination will significantly affect mitochondrial quality control-related proteins in the liver compared to the glucose-intolerant animals. Methods: A low dose of streptozotocin (30mg/kg) and a high-fat diet (45% kcal from fat) were used to induce hyperglycemia in male Sprague Dawley rats. The rats were divided into four groups: vehicle sedentary (VEH SED; n=10), vehicle exercise (VEH EX; n=7), SGLT2i sedentary (SGLT2i SED; n=10), and SGLT2i exercise (SGLT2i EX; n=7). SGLT2i groups received 3mg/kg/day of canagliflozin in 0.5% methylcellulose via oral gavage. The EX-groups exercised for 60 minutes per day, 5 days a week on a 10% incline, at ~50 maximal running speed obtained from a VO 2 max test, Treatments lasted for 12 weeks. Results: We previously reported that EX, SGLT2i, and combination therapy improved metabolic glycemic regulation in these animals which may have contributed to less mitochondrial damage and better mitochondrial function.EX had ~10% higher hepatic expression of pro-fission protein total DRP1 and ~15% higher expression of fusion protein MFN2, however, these did not reach significance (p=0.06 and p=0.08 respectively, main effect of EX). Although not significant, SGLT2i had ~30% higher expression of pro-fission protein Fis1 (p=0.12). SGLT2i had lower expression of the fusion protein MFN1 (p<0.01, main effect of SGLT2i). In the liver, EX, SGLT2i, and the combination therapy did not affect the protein expression of pro-fission proteins pDRP-1 (Ser616), pDRP-1/total DRP1, MFF and pMFF, or the pro-fusion protein Opa1. EX had higher expression of autophagy-related Pink1 (p<0.01 vs SED) and LC3B-I (p<0.05 vs SED) in the liver. SGLT2i had higher expression of autophagy-related protein BNIP3 (p<0.05, main effect of SGLT2i). EX, SGLT2i, and the combination therapy did not affect the protein expression of autophagy-related LC3B-II, the LC3B-II/LC3B-I ratio, or parkin. Conclusion: Our data suggest that, following twelve weeks of treatment, the SGLT2 inhibitor (SGLT2i) and exercise (EX) independently affected the expression of mitochondrial quality control-related proteins (i.e., fission, fusion, and autophagy-related) in the liver of a rat model of glucose intolerance, as combination therapy did not show any synergistic effects or additional benefits. This work was partially supported by Pfizer Inc. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.