Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice

Abstract

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

The antidiabetic SGLT2 inhibitor canagliflozin reduces mitochondrial metabolism in a model of skeletal muscle insulin resistance

“…17 In vitro, CANA may reduce ATP production and fragment mitochondria in a way unique to CANA (observations not seen in either dapagliflozin or empagliflozin). 3 These observations were also found in HUVEC cells, which is in line with our observations. 4 Collectively, we observed reduced cell metabolism which occurred independently of changes in related gene expression.…”

“…In vitro, CANA has been shown to down‐regulate expression of genes which govern myotube formation 3 . This observation may be in part due to the possibility that CANA alters cellular energetics.…”

“…2 In vitro, CANA has been shown to down-regulate expression of genes which govern myotube formation. 3 This observation may be in part due to the possibility that CANA alters cellular energetics. For example, CANA may reduce ATP production and lead to fragmented mitochondria with reduced mitochondrial function.…”

“…For example, CANA may reduce ATP production and lead to fragmented mitochondria with reduced mitochondrial function. 3 Interestingly, Lv et al demonstrated that diminished mitochondrial function may be unique to CANA as neither dapagliflozin nor empagliflozin reduced mitochondrial function nor did either produced more fragmented mitochondria (though all of the gliflozins reduced ATP content in myoblast). 3 Similarly, other observations in HUVEC cells showed that CANA was uniquely potent at inhibiting mitochondrial function and glycolytic metabolism.…”

“…3 Interestingly, Lv et al demonstrated that diminished mitochondrial function may be unique to CANA as neither dapagliflozin nor empagliflozin reduced mitochondrial function nor did either produced more fragmented mitochondria (though all of the gliflozins reduced ATP content in myoblast). 3 Similarly, other observations in HUVEC cells showed that CANA was uniquely potent at inhibiting mitochondrial function and glycolytic metabolism. 4 Ex vivo observations have assessed the effect of dapagliflozin on isolated mitochondrial from vastus lateralis muscle of participants with diabetes and found unchanged respiration, citrate synthase activity and mitochondrial fragmentation.…”