494-P: Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular Matrix Accumulation and Restores the Adaptive Response to Aerobic Exercise

Abstract

In rodent models and humans, hyperglycemia is associated with an impaired adaptive response to aerobic exercise, which includes blunted improvements in aerobic capacity and impaired aerobic remodeling of skeletal muscle. To test whether glucose lowering therapy can restore the response to exercise, aerobic training studies were performed on hyperglycemic mice treated with or without the SGLT2 inhibitor, Canagliflozin (CANA) for 16-wks. Hyperglycemia was induced using two injections of streptozotocin (STZ; 40 mg/kg). A cohort of STZ-treated mice were administered CANA in their food (30 mg/kg/day), which normalized blood glucose to the level of untreated normoglycemic controls. The adaptive response to aerobic exercise training was blunted in STZ compared to control, but was restored by CANA treatment. Following training, CANA had improved aerobic exercise capacity (VO2peak), higher capillary density in cardiac and skeletal muscle, and a more oxidative fiber-type in skeletal muscle, compared to STZ. Recent work implicates glucose-induced accumulation of the skeletal muscle extracellular matrix (ECM), leading to hyper-activation of JNK/SMAD2 mechanical signaling after acute exercise as potential mechanisms underlying low exercise response. Consistent with this, STZ had significant accumulation of muscle ECM compared to control which was prevented by treatment with CANA, as assessed by histological staining. In addition, hyper-activation of JNK/SMAD2 mechanical signaling after a bout of acute exercise was 2-fold higher in STZ compared to control, but was normalized by CANA. These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by Canagliflozin treatment. Moreover, we identify skeletal muscle ECM accumulation and JNK/SMAD2 hyper-activation as potential mechanisms for impaired aerobic adaptation with hyperglycemia. Disclosure T. Macdonald: None. P. Pattamaprapanont: None. S. J. Lessard: None. Funding National Institutes of Health (R01DK124258)