Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.

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.

Activation of spinal NF-КB mediates pain behavior induced by plantar incision.

A growing body of evidence indicates that the activation of nuclear factor kappa B (NF-κB) pathway was involved in neuropathic and inflammatory pain, however, the role of NF-κB in incisional pain is still unclear. Therefore, in this study, we investigated whether the activation of NF-κB in the spinal cord is involved in pain hypersensitivity after a plantar incision in the rat hind paw. After rats received a plantar incision surgery, mechanical allodynia and thermal hyperalgesia were determined by von Frey filaments and radiant heat, respectively. Western blot was used to determineNF-κB activation at different time points after incision. The NF-κB inhibitor pyrrolidinedithiocarbamate (PDTC) was administered intrathecally 30 min before hind paw plantar incision to determine the role of NF-κB in incision-induced pain. Our results showed that the expression level of NF-κB was significantly increased in spinal cord dorsal horn from 30 min to 3 days after the incision. Intrathecal pretreatment of PDTC attenuated incision-induced mechanical allodynia and thermal hyperalgesia. Furthermore, PDTC significantly reduced the expression level of c-Fos in the dorsal horn after plantar incision. Taken together, plantar incision-induced pain behaviors can be prevented by the NF-κB inhibitor. Our results suggest that the blockage of the NF-КB signaling pathway might represent a valuable alternative for treating postoperative pain.