Downregulation of HSPA12A underlies myotoxicity of local anesthetic agent bupivacaine through inhibiting PGC1α-mediated mitochondrial integrity.
Downregulation of HSPA12A underlies myotoxicity of local anesthetic agent bupivacaine through inhibiting PGC1α-mediated mitochondrial integrity.
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DOI：
10.1016/j.taap.2021.115798
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发表时间：
2021-11
影响因子：
3.8
通讯作者：
Q. Mao;Wansu Yu;Shijiang Liu;Xiaofei Cao;Yuan Dai;Xiaojin Zhang;Xinxu Min;Li Liu;Zhengnian Ding
中科院分区：
文献类型：
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作者：
Q. Mao;Wansu Yu;Shijiang Liu;Xiaofei Cao;Yuan Dai;Xiaojin Zhang;Xinxu Min;Li Liu;Zhengnian Ding
局麻药广泛应用于术中麻醉和术后镇痛。然而，LAs（如布比卡因）可引起与线粒体损伤密切相关的肌毒性。PGC1a是线粒体质量控制的桅杆辅助因子。我们最近证明肝细胞中的PGC1a可以被HSPA12A激活，这表明HSPA12A可能通过激活pgc1 α介导的线粒体完整性来保护LAs肌毒性。在这里，我们报道了HSPA12A在布比卡因诱导的小鼠骨骼肌体内和体外培养的C2c12成肌细胞的肌毒性中下调。有趣的是，HSPA12A的过表达减轻了布比卡因诱导的C2c12细胞死亡。我们还注意到，过量表达HSPA12A可以改善布比卡因诱导的葡萄糖消耗和ATP产生的减少。此外，C2c12细胞中HSPA12A的过表达减弱了布比卡因引起的线粒体含量下降和线粒体断裂增加。过表达HSPA12A可明显减弱布比卡因诱导的PGC1α表达和核定位的降低。重要的是，使用选择性PGC1α抑制剂（SR-18292）预处理可以消除HSPA12A对布比卡因诱导的C2c12细胞死亡和线粒体丢失的保护作用。综上所述，研究结果表明HSPA12A的下调通过抑制pgc1 α介导的线粒体完整性而成为局麻药布比卡因肌毒性的基础。因此，HSPA12A可能是一种预防LAs肌毒性的可行策略。
Local anesthetics (LAs) are widely used for intraoperative anesthesia and postoperative analgesia. However, LAs (e.g.Bupivacaine) can evoke myotoxicity that closely associated to mitochondrial damage. PGC1a is a mast co-factor for mitochondrial quality control. We have recently demonstrated that PGC1a can be activated by HSPA12A in hepatocytes, suggesting a possibility that HSPA12A protects from LAs myotoxicity through activating PGC1α-mediated mitochondrial integrity. Here, we reported that HSPA12A was downregulated during Bupivacaine-induced myotoxicity in skeletal muscles of micein vivoand C2c12 myoblast culturesin vitro. Intriguingly, overexpression of HSPA12A attenuated the Bupivacaine-induced C2c12 cell death. We also noticed that the Bupivacaine-induced decrease of glucose consumption and ATP production was improved by HSPA12A overexpression. Moreover, overexpression of HSPA12A in C2c12 cells attenuated the Bupivacaine-induced decrease of mitochondrial contents and increase of mitochondrial fragmentation. The Bupivacaine-induced reduction of PGC1α expression and nuclear localization was markedly attenuated by HSPA12A overexpression. Importantly, pretreatment with a selective PGC1α inhibitor (SR-18292) abolished the protection of HSPA12A from Bupivacaine-induced death and mitochondrial loss in C2c12 cells. Altogether, the findings indicate that downregulation of HSPA12A underlies myotoxicity of Local anesthetic agent Bupivacaine through inhibiting PGC1α-mediated Mitochondrial Integrity. Thus, HSPA12A might represent a viable strategy for preventing myotoxicity of LAs.