UC San Diego

Sodium Glucose Transporter 2 (SGLT2) inhibitors are commonly prescribed to reduce hyperglycemia in patients with type 2 diabetes (T2D). Though SGLT2 is localized exclusively in the kidneys, SGLT2 inhibitors have known off-target effects in other tissues, such as cardiac and skeletal muscle. Skeletal muscle is heavily implicated in the progression of T2D, but little research has examined the effects of SGLT2 inhibitors on skeletal muscle physiology. To address this gap in knowledge, we examined the effects of the SGLT2 inhibitors canagliflozin (CANA) and empagliflozin (EMPA) on skeletal muscle contractile function and fatigability in the soleus (SOL) and extensor digitorum longus (EDL) muscles from 14-17 week-old male (n=23) and female mice (n=24). Using an ex vivo approach, we measured sub-maximal and maximal force generation via a force-frequency test (1-100 or 1-120 Hz stimulation frequency in SOL or EDL, respectively) and fatigability (submaximal contraction every 2 or 4 seconds for 15 min in SOL or EDL, respectively) after muscles were pre-incubated for 60 min in Vehicle (VEH; dimethyl sulfoxide [0.05% final concentration]), CANA (5 μM), or EMPA (5 μM); incubation in VEH, CANA, or EMPA was maintained during the contractile testing protocol. As compared to VEH, there was no effect of CANA or EMPA on SOL, regardless of sex. There was a 21% reduction in the time-to-fatigue of male EDL treated with EMPA, but not CANA. Together, these results indicate that there are sex-, SGLT2 inhibitor type-, and fiber type-dependent effects of SGLT2 inhibitors on skeletal muscle fatigability.