Exercise And Sglt2 Inhibitor Therapy Independently Affect Mitochondrial Quality Control In Soleus And Heart

Mitochondrial dysfunction is associated with diseases such as type 2 diabetes (T2D). Exercise training (EX) and sodium glucose cotransporter-2 inhibitors (SGLT2i) are therapies that improve T2D and have cardiovascular effects. However, it remains unclear how SGLT2i therapy may affect regulators of mitochondrial quality (mitochondrial fission, fusion, mitophagy) alone and with EX. PURPOSE: To assess the effects of SGLT2i therapy, EX, and the combination on mitochondrial quality control in the soleus and cardiac tissues in a model of T2D. METHODS: Male Sprague-Dawley rats were given a low-dose of streptozotocin (30 mg/kg) and high-fat diet (45% kcal from fat) to induce hyperglycemia. Animals were assigned to a vehicle sedentary (VEH SED), vehicle exercise (VEH EX), SGLT2i sedentary (SGLT2i SED), and an SGLT2i exercise group (SGLT2i EX) and underwent therapies for 12 wks. SGLT2i animals received 3 mg/kg/d of canagliflozin in 0.5% methylcellulose via oral gavage, while VEH received only 0.5% methylcellulose. EX ran 60 min/d, 5d/wk on a 10% incline. RESULTS: In the soleus, EX had ~80% higher expression of the pro- fission protein pDRP-1 (ser616), however this did not reach significance (p = 0.057 main effect EX). Neither EX nor SGLT2i had effects on other fission proteins (Fis1, MFF) or the fusion protein Opa1. EX had higher expression of the autophagy-related LC3B-I and LC3B-II in the soleus (p < 0.05). LC3B-II was only higher in VEH EX compared to VEH SED (1.74 vs 1.06), while LCB3-II was similar between VEH SED and the SGLT2i treated groups (interaction p = 0.037). SGLT2i had ~50% lower expression of Fis1 (p = 0.0099 main effect SGLT2i) in cardiac tissue. Neither Ex nor SGLTG2i therapy had effects on other fission or fusion proteins assessed in cardiac tissue. There was a significant interaction seen with BNIP3 protein (p = 0.022) in cardiac tissue. BNIP3 protein expression was ~45% higher in VEH EX and SGLT2i SED when compared to VEH SED (p < 05). CONCLUSION: Twelve weeks of SGLT2i treatment or EX had independent effects on indices of mitochondrial quality control in soleus and cardiac muscles. This work was supported by Pfizer Inc