Canagliflozin Prevents Hyperglycemia-Associated Muscle Extracellular Matrix Accumulation and Improves the Adaptive Response to Aerobic Exercise

Abstract

Chronic hyperglycemia is associated with low response to aerobic exercise training in rodent models and humans, including reduced aerobic exercise capacity and impaired oxidative remodeling in skeletal muscle. Here, we investigated whether glucose lowering with the sodium glucose cotransporter-2 inhibitor (SGLT2i), canagliflozin (Cana; 30 mg/kg/day), could restore exercise training response in a model of hyperglycemia (low dose streptozotocin; STZ). Cana effectively prevented increased blood glucose in STZ-treated mice. After 6 weeks of voluntary wheel running, Cana-treated mice displayed improvements in aerobic exercise capacity, higher capillary density in striated muscle, and a more oxidative fiber-type in skeletal muscle. In contrast, these responses were blunted or absent in STZ mice. Recent work implicates glucose-induced accumulation of skeletal muscle extracellular matrix (ECM) and hyper-activation of JNK/SMAD2 mechanical signaling as potential mechanisms underlying poor exercise response. In line with this, muscle ECM accretion was prevented by Cana in STZ-treated mice. JNK/SMAD2 signaling with acute exercise was 2-fold higher in STZ compared to Control but was normalized by Cana. In human participants, ECM accumulation was associated with increased JNK signaling, low VO2peak and impaired metabolic health (siOGTT). These data demonstrate that hyperglycemia-associated impairments in exercise adaptation can be ameliorated by co-therapy with SGLT2i.

Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

“…It has been suggested that SGLT2 inhibition could ameliorate the remodeling of skeletal muscle. In a mouse model with reduced aerobic exercise capacity due to chronic hyperglycemia, treatment with canagliflozin led to an increase in the proportion of oxidative fibers, suggesting that impaired muscle remodeling was prevented by treatment with SGLT2 inhibitors [ 169 ]. In a high-fat diet mouse model in which mice were treated with canagliflozin for 8 weeks, SGLT2 inhibition induced a reduction in inflammatory cytokine levels and macrophage accumulation [ 170 ].…”

“…Decreasing oxidative stress or inflammation could have a beneficial effect in preventing a shift in muscle fiber type in skeletal muscle [ 170 ]. Furthermore, treatment with canagliflozin was found to restore exercise-induced angiogenesis in mice that were exposed to hyperglycemia [ 169 ]. The question of whether SGLT2 inhibitors could have similar effects on amelioration of the HF-induced remodeling in skeletal muscle has not yet been studied.…”

“…To our knowledge, the effect of SGLT2 inhibitors on oxidative muscle metabolism in HF patients has not been assessed. Interestingly, in streptozotocin-treated mice, SGLT2 inhibitor treatment led to a restoration of the training response [ 169 ]. In this study, mice were treated with canagliflozin for 8 weeks and exercise capacity was assessed before and after 6 weeks of voluntary wheel running.…”

“…Lastly, the discussed experimental study that showed that SGLT2 inhibition improves the training response suggests that SGLT2 inhibitors could potentially also play a beneficial role in the effectiveness of HF rehabilitation in the clinic [ 169 ]. This hypothesis is supported by the observed effects on the improvement of oxidative skeletal muscle metabolism and the observed switch from the glycolytic to the oxidative energy production system after treatment with SGLT2 inhibitors.…”

Improved endurance capacity of diabetic mice during SGLT2 inhibition: Role of AICARP, an AMPK activator in the soleus

“…These observations suggest that the metabolic effect of SGLT2 inhibitors on skeletal muscle depends on glucose availability. Several studies have reported that SGLT2 inhibitors can improve the endurance capacity of streptozotocin (STZ)‐induced hyperglycaemic mice 12,13 . However, there is no detailed analysis of how SGLT2 inhibitors affect skeletal muscle metabolism in obese diabetic mice focusing on the differential responses of oxidative and glycolytic muscles.…”