Research Institute of Experimental Neurobiology, Department of Neurology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang Provincial Key Lab for Tissue Engineering and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Acta Pharmacol Sin. 2022 Oct;43(10):2651-2665. doi: 10.1038/s41401-022-00878-7. Epub 2022 Feb 25.
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.
卡格列净是一种抗糖尿病药物，可抑制近端肾小管中的钠-葡萄糖共转运蛋白 2 (SGLT2)。最近，有报道称其具有除 SGLT2 抑制以外的几种非典型作用。然而，卡格列净对骨骼肌再生的影响在很大程度上仍未得到探索。因此，评估了格列净治疗后小鼠缺血下肢肌肉收缩特性的恢复情况。还评估了格列净处理后 C2C12 成肌细胞的分化情况。结果表明，体内和体外数据均表明卡格列净会损害固有肌生成，从而阻碍缺血肢体肌肉收缩特性、抗疲劳能力的恢复和组织再生。卡格列净还会破坏成肌细胞中的线粒体结构和活性。缺血性比目鱼肌的单细胞 RNA 测序显示，肌肉干细胞中的亮氨酰-tRNA 合成酶 2 (LARS2)因卡格列净而减少。进一步的研究阐明了 LARS2 的非典型功能，它通过影响线粒体结构和活性在调节成肌细胞分化和肌肉再生中发挥关键作用。增强 LARS2 的表达可恢复卡格列净处理的成肌细胞的分化，并加速卡格列净处理的小鼠缺血性骨骼肌再生。我们的数据表明，卡格列净通过下调肌肉干细胞中的 LARS2 表达直接损害小鼠的缺血性骨骼肌恢复，并且 LARS2 可能是受伤骨骼肌再生的有前途的治疗靶点。
