Erythromycin Increases Muscle Endurance by Upregulating Orosomucoid (ORM) to Act on C-C Chemokine Receptor Type 5

Abstract

Background: At present, there are still no official or semi-official recommendations for the treatment of muscle fatigue. We previously reported that acute phase protein orosomucoid (ORM) can enhance muscle endurance and exert anti-fatigue effect, but with limited clinical application. Here, we try to seek anti-fatigue drugs that target ORM, and further clarify its potential mechanism. Methods: Weight-loaded forced swimming and electrically evoking of isolated soleus muscle contractions were applied to measure fatigue levels. Electron microscopy was used to observe tissue damage. Western blotting and ELISA were applied to evaluate protein levels. Glycogen content was detected by assay kit. Dual luciferase reporter assays were used to explore the effect of erythromycin on ORM reporter. Findings: Erythromycin can significantly prolong mice forced-swimming time, increase muscle fatigue index, alleviate fatigue-induced tissue damage, and promote glycogen storage in liver and muscle. Further studies showed that erythromycin could increase ORM expression in a dose- and time- dependent manner both in vitro and in vivo, which might result from a positive transcriptional regulation in ORM promoter. ORM knockdown or knockout could abolish the promoting effect of erythromycin in mice forced-swimming time, muscle fatigue index and glycogen storage. Furthermore, those effects were also abolished in mice with CCR5 antagonist administration or AMPKI±2 deficiency. Interpretation: Erythromycin could enhance muscle glycogen and endurance via up-regulating the level of ORM and activating CCR5-AMPK pathway, indicating it might act as a potential drug to treat muscle fatigue. Funding Statement: This study was supported by grants from the National Science and Technology Major Project (No. 2018ZX09J18110-03), National Natural Science Foundation of China (No.81773726;81603116) and the Young Elite Scientists Sponsorship Program by CAST (No.2017QNRC001). Declaration of Interests: The authors report they have nothing to disclose. Ethics Approval Statement: The experimental procedures were approved by the Laboratory Animal Care and Use Committee of the Second Military Medical University, China. Animal studies are performed in compliance with the APPRIVE guidelines.