Differential effect of canagliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on slow and fast skeletal muscles from nondiabetic mice

Abstract

There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.

Association between SGLT2 Inhibitors and Cardiac Rehabilitation Outcomes in Patients with Cardiovascular Disease and Type 2 Diabetes Mellitus

“…A marked decrease in lean mass was observed with high doses of canagliflozin [ 9 ]. Several researchers have investigated the effect of SGLT2 inhibitors on skeletal muscle mass and function in mice [ 12 , 27 , 28 ]. Interestingly, Bamba et al showed that the db/db young mice fed a diet with SGLT2 inhibitors had higher skeletal muscle mass [ 28 ], while Nambu et al found no significant effect in muscle mass of HF model mice [ 27 ].…”

“…Interestingly, Bamba et al showed that the db/db young mice fed a diet with SGLT2 inhibitors had higher skeletal muscle mass [ 28 ], while Nambu et al found no significant effect in muscle mass of HF model mice [ 27 ]. Contrary to these studies, Otsuka et al reported that when the amount of food in SGLT2 inhibitor-treated mice was adjusted to that in vehicle-treated mice, muscle mass and function were reduced in the treated mice [ 12 ]. Muscle mass reduction was found in the tibialis anterior and extensor digitorum longus muscles but not in the soleus muscle, indicating a muscle-fiber-type-specific change [ 12 ].…”

“…Contrary to these studies, Otsuka et al reported that when the amount of food in SGLT2 inhibitor-treated mice was adjusted to that in vehicle-treated mice, muscle mass and function were reduced in the treated mice [ 12 ]. Muscle mass reduction was found in the tibialis anterior and extensor digitorum longus muscles but not in the soleus muscle, indicating a muscle-fiber-type-specific change [ 12 ]. When food intake in the treated group was intentionally adjusted to the control group, protein degradation exceeded protein synthesis as a catabolic response to SGLT2 inhibition, likely causing skeletal muscle mass loss in mice [ 12 ].…”

“…However, previous studies on type 2 diabetes mellitus (T2DM) have shown a decrease in skeletal muscle mass with SGLT2 inhibitors [ 9 , 10 , 11 ]. In addition to reduced skeletal muscle mass, mice with adjusted dietary intake have also shown muscle weakness [ 12 ]. However, it remains unclear as to how SGLT2 inhibitors affect changes in skeletal muscle mass and physical function, while there is concern that SGLT2 inhibitors may reduce physical function.…”

Could SGLT2 Inhibitors Improve Exercise Intolerance in Chronic Heart Failure?

“…Another study in T2DM patients even showed a small decrease in skeletal muscle mass after luseogliflozin treatment for 36 weeks [ 181 ]. Recently, Otsuka et al showed that, in healthy mice treated with canagliflozin, grip strength was unaffected during ad libitum feeding while a significant reduction was present when mice were pair-fed in the same amounts as vehicle-treated controls [ 182 ]. Interestingly, glycolytic type II muscle fiber mass and function were affected, while oxidative type I muscles remained unaffected.…”