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.
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27 June 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41401-024-01320-w
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Acknowledgements
We gratefully acknowledge the team of the Scientific Research Center of Wenzhou Medical University for their technical and scientific expertise in the immunocytochemistry study. This study was financially supported by the National Natural Science Foundation of China (82070493, 82102564, 81800314), Natural Science Foundation of Zhejiang Province (LY21H020008), and Wenzhou Municipal Science and Technology Bureau Foundation (ZY2020016, Y20210161).
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YNL, ZZL, and XC conceived and designed the project. XHL, XXC, JLN, XML performed the experiments. BBW performed the transmission electron microscopy analysis. RYZ performed animal anesthesia. JS and QLZ performed the animal models. WAC provided supervision of the study. YNL, LS, and ZTW wrote the manuscript, with contributions from all other authors.
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Lv, Xh., Cong, Xx., Nan, Jl. et al. Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice. Acta Pharmacol Sin 43, 2651–2665 (2022). https://doi.org/10.1038/s41401-022-00878-7
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DOI: https://doi.org/10.1038/s41401-022-00878-7
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