Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling

Qiuxian Wan; Lilei Zhang; Ziwei Huang; Haiyan Zhang; Jing Gu; Hua Xu; Xiaoming Yang; Yuntian Shen; Betty Yuen-Kwan Law; Jianwei Zhu; Hualin Sun

doi:10.21037/atm-20-5460

Aspirin alleviates denervation-induced muscle atrophy via regulating the Sirt1/PGC-1α axis and STAT3 signaling

Ann Transl Med. 2020 Nov;8(22):1524. doi: 10.21037/atm-20-5460.

Authors

Qiuxian Wan^{1

2}, Lilei Zhang¹, Ziwei Huang¹, Haiyan Zhang^{1

2}, Jing Gu², Hua Xu³, Xiaoming Yang¹, Yuntian Shen¹, Betty Yuen-Kwan Law⁴, Jianwei Zhu³, Hualin Sun¹

Affiliations

¹ Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
² Department of Medical Laboratory, School of Public Health, Nantong University, Nantong, China.
³ Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.

Abstract

Background: Our prior studies have shown that inflammation may play an important triggering role during the process of denervated muscle atrophy. The nonsteroidal anti-inflammatory drug aspirin exhibits the effect of anti-inflammatory factors. This study will investigate the protective effect of aspirin on denervated muscle atrophy and the underlying mechanism.

Methods: Mouse models of denervated muscle atrophy were established. The protective effect of aspirin (20 mg/kg/d, i.p.) on denervated muscle atrophy was analyzed using the wet weight ratio of tibialis anterior (TA) muscle and muscle fiber cross-sectional area (CSA). The levels of inflammatory factors were detected using quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Sirtuins1 (SIRT1)/Peroxisome Proliferator-Activated Receptor γ Co-Activator 1α (PGC-1α) and Signal transducer and activator of transcription 3 (STAT3) signaling pathway and the muscle fiber type related proteins in TA muscle after denervation were analyzed by western blot assay.

Results: Intraperitoneal injection of aspirin (20 mg/kg/d) effectively alleviated denervation-induced muscle atrophy. This mainly manifested as follows: The wet weight ratio of TA muscle and muscle fiber CSA of mice treated with aspirin were significantly greater compared with mice treated with normal saline. The level of myosin heavy chain (MHC) increased, and the levels of muscle specific E3 ubiquitin ligase Muscle-specific RING finger-1 (MuRF-1) and muscle atrophy F-box (MAFbx) were decreased. Mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy related proteins PINK1, BNIP3, LC3B and Atg7 in mice treated with aspirin compared with mice treated with saline. In addition, aspirin treatment inhibited the slow-to-fast twitch muscle fiber conversion, which were related with triggering the expression of Sirt1 and PGC-1α. Moreover, aspirin reduced the levels of inflammatory factors interleukin-6, interleukin-1β and tumor necrosis factor-α and decreased the activation of STAT3 signaling pathway.

Conclusions: This is the first study to find that aspirin can alleviate denervation-induced muscle atrophy and inhibit the type I-to-type II muscle fiber conversion and mitophagy possibly through regulating the STAT3 inflammatory signaling pathway and Sirt1/PGC-1α signal axis. This study expands our knowledge regarding the pharmacological function of aspirin and provides a novel strategy for prevention and treatment of denervated muscle atrophy.

Keywords: Peripheral nerve injury; aspirin; inflammatory reaction; muscle atrophy.