Sodium-glucose Cotransporter-2 Inhibition Slows Protein Synthesis In Skeletal And Cardiac Muscle Independent Of Exercise Training

Tissue proteostasis is associated with health and longevity, and exercise can affect proteostasis. Treatment with a sodium-glucose cotransporter- 2 inhibitor (SGLT2i), a diabetes medication, has extended lifespan in rodents. PURPOSE: to assess if SGLT2i therapy in combination with aerobic exercise training (EX) changes protein synthesis rates in skeletal and cardiac tissue when compared to exercise or SGLT2i treatment alone. METHODS: Male Sprague-Dawley rats were given a low dose of streptozotocin (30 mg/kg) with a high fat diet to induce hyperglycemia and then assigned to vehicle sedentary (VEH SED), VEH EX, SGLT2i SED (3 mg/kg/d canagliflozin), or SGLT2i EX groups for 12 weeks (n = 15-19 animals/group). EX ran 60 min/d, 5d/wk on a 10% incline. Stable isotope assessments were used to determine protein synthesis rates. RESULTS: SGLT2i had lower rates of protein synthesis in cytosolic (k = 0.033 vs 0.040 1/day) and mixed protein fractions (k = 0.027 vs 0.035 1/day) in the gastrocnemius-plantaris complex (p < 0.05) and tended to have lower protein synthesis rates in the mixed fraction of the soleus (p = 0.098) compared to VEH. There were no differences in protein synthesis rates of the mitochondrial fraction of the gastrocnemius-plantaris complex or the mitochondrial or cytosolic protein fractions in the soleus. In the heart, SGLT2i had lower protein synthesis rates in the mitochondrial fraction compared to the VEH (k = 0.048 vs 0.060 1/day, p < 0.05); there were no differences in the mixed and cytosolic fractions. EX had no effects on protein synthesis rates (p > 0.05) while there was a significant interaction in heart mitochondrial protein synthesis rates (p < 0.05). The phosphorylation status of key proteins related to mTOR signaling, RPs6 and 4EBP-1, did not differ between groups in the gastrocnemius-plantaris complex or heart, SGLT2i had lower pRPs6/total RPs6 than VEH in the soleus (0.88 vs 1.87 AU, p < 0.05). CONCLUSION: EX had no effect on protein synthesis rates in this model. However, SGLT2i slowed protein synthesis rates in skeletal muscle and heart and may serve as a means by which SGLT2i therapy could slow aging. This work was supported by NIH T32 DK064584 and the American Physiological Society STRIDE fellowship. We would like to thank William Esler and Benjamin Miller for their scientific insight.