1. Academic Validation
  2. 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

  • Toxicol Appl Pharmacol. 2022 Jan 1;434:115798. doi: 10.1016/j.taap.2021.115798.
Qian Mao 1 Wansu Yu 2 Shijiang Liu 1 Xiaofei Cao 1 Yuan Dai 1 Xiaojin Zhang 2 Xinxu Min 1 Li Liu 3 Zhengnian Ding 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
  • 2 Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
  • 3 Department of Geriatrics, Jiangsu Provincial Key Laboratory of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China; Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing 210029, China.
  • 4 Department of Anesthesiology, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China. Electronic address: zhengnianding@njmu.edu.cn.
Abstract

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 mice in vivo and C2c12 myoblast cultures in 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.

Keywords

HSPA12A; Local anesthetics; Mitochondria; Myotoxicity; PGC1α.

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