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.

Xin-huang Lv;Xiao-xia Cong;Jin-liang Nan;Xing-mei Lu;Qian-li Zhu;Jian Shen;Bei-bei Wang;Zhi-ting Wang;Ri-yong Zhou;Wei-an Chen;Lan Su;Xiao Chen;Zheng-zheng Li;Yi-nuo Lin

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;Department of Pathology,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou 325000,China;ProvincialKey Cardiovascular Research Laboratory,Department of Cardiology,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China;Wenzhou Municipal Key Cardiovascular Research Laboratory,Department of Cardiology,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou 325000,China;Center of Cryo-Electron Microscopy,Zhejiang University,Hangzhou 310058,China;Department of Anesthesiology,The First Affiliated Hospital,Wenzhou Medical University,Wenzhou 325000,China

中国药理学报（英文版）

[1]Xin-huang Lv;Xiao-xia Cong;Jin-liang Nan;Xing-mei Lu;Qian-li Zhu;Jian Shen;Bei-bei Wang;Zhi-ting Wang;Ri-yong Zhou;Wei-an Chen;Lan Su;Xiao Chen;Zheng-zheng Li;Yi-nuo Lin-.Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice)[J].中国药理学报（英文版）,2022(10):2651-2665

canagliflozin,Canagliflozin,gliflozins,leucyl,LARS2

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