Activation of Opioid Receptors Attenuates Ischemia/Reperfusion Injury in Skeletal Muscle Induced by Tourniquet Placement

Yue-Xian Guo, Gui-Ying Wang, Wen-Jie Cheng, Cai-Zhen Yan, Shuang Zhao, Zhao Li, Peng Liu, Xiu-Li Wang, Yue-Xian Guo, Gui-Ying Wang, Wen-Jie Cheng, Cai-Zhen Yan, Shuang Zhao, Zhao Li, Peng Liu, Xiu-Li Wang

Abstract

Method: Mice were randomly assigned to the sham, I/R, Oxy, and I/R with Oxy groups. Oxy was injected intraperitoneally 30 min before tourniquet placement. Morphological changes of the gastrocnemius muscle in these mice were assessed by hematoxylin-eosin (HE) staining and electron microscopy. Expression levels of TLR4, NF-κB, SIRT1, and PGC-1α in the skeletal muscles were detected by western blot. Blood TNF-α levels, gastrocnemius muscle contractile force, and ATP concentration were examined.

Results: Compared with the I/R group, Oxy pretreatment attenuated skeletal muscle damage, decreased serum TNF-α levels, and inhibited the expression levels of TLR4/NF-κB in the gastrocnemius muscle. Furthermore, Oxy treatment significantly increased serum ATP levels and the contractility of the skeletal muscles. SIRT1 and PGC-1α levels were significantly reduced in gastrocnemius muscle after I/R. Oxy pretreatment recovered these protein expression levels.

Conclusion: Tourniquet-induced acute limb I/R results in morphological and functional impairment in skeletal muscle. Pretreatment with Oxy attenuates skeletal muscle from acute I/R injury through inhibition of TLR4/NF-κB-dependent inflammatory response and protects SIRT1/PGC-1α-dependent mitochondrial function.

Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this article.

Copyright © 2021 Yue-Xian Guo et al.

Figures

Figure 1
Figure 1
Oxy treatment increased blood flow after tourniquet placement on the hind limb. (a) Representative images of blood perfusion in the mouse hind limb obtained using laser speckle contrast imaging. The red color on the image represents high blood flow to the limb while the blue color represents low blood flow. Quantification of perfusion in the ischemic hind limb before ischemia (b), during ischemia (c), and during reperfusion for 24 h (d). I/R: ischemia-reperfusion; Oxy: oxycodone. Data are expressed as the mean ± SEM (n = 6 in each group); ∗P < 0.05 vs. sham.
Figure 2
Figure 2
Morphology changes in gastrocnemius muscle tissues in response to tourniquet placement. (a) Representative histology in longitudinal and transverse sections of gastrocnemius muscles stained with hematoxylin-eosin. (b) Representative histology in cross and lengthwise sections of gastrocnemius muscles stained with Masson's trichrome. Arrows indicate the site of muscle injury. (c) Summary data of histology damage scores in sham, I/R, and I/R plus Oxy groups. I/R: ischemia-reperfusion; Oxy: oxycodone (n = 6 in each group).
Figure 3
Figure 3
Electron microscope images of the gastrocnemius muscle tissues from all experimental groups. The scale was 667 nm at 15,000 magnification. I/R: ischemia-reperfusion; Oxy: oxycodone (n = 6 in each group).
Figure 4
Figure 4
Oxy treatment attenuated alteration of TNF-α and ATP concentration induced by tourniquet placement. (a) Serum TNF-α level. (b) Concentration of ATP in gastrocnemius muscles. I/R: ischemia-reperfusion (n = 6 in each group); ∗P < 0.05 vs. sham; #P < 0.05 vs. I/R. Oxy: oxycodone.
Figure 5
Figure 5
Oxy attenuated impairment of contractility of gastrocnemius muscles induced by a tourniquet. (a) Schematic diagram of experimental setup. (b) Individual twitch contraction of the gastrocnemius muscle. (c) Tetanic contractile force. (d, e) Quantitative analysis of individual twitch contractile force and tetanic contractile force in different groups. I/R: ischemia-reperfusion; Oxy: oxycodone. Data are expressed as the mean ± SE (n = 6 in each group); ∗P < 0.05 vs. sham; #P < 0.05 vs. I/R.
Figure 6
Figure 6
Oxy treatment decreased TLR4 and NF-κB expression levels while increasing SIRT1 and PGC-1α levels in tourniquet-induced I/R in gastrocnemius muscle tissues. (a) Representative band images for TLR4, NF-κB, SIRT1, and PGC-1α in the I/R and Oxy-treated I/R groups. (b–e) Summary data showing expression of TLR4 (b), NF-κB (c), SIRT1 (d), and PGC-1α (e). I/R: ischemia-reperfusion; Oxy: oxycodone. Data are expressed as the mean ± SE (n = 6 in each group); ∗P < 0.05 vs. sham; #P < 0.05 vs. I/R.

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