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CXCR3通过调控E3泛素连接酶、生肌因子及脂肪酸β-氧化途径改善顺铂诱导的骨骼肌萎缩

徐苗苗^1,2, 刘晓光³, 陆丽明², 李兆伟^1,*

¹广州中医药大学体育与健康学院，广州 510006；²广州中医药大学针灸康复临床医学院，广州 510006；³广州体育学院运动健康学院，广州 510620

摘要

本研究旨在探讨CXC趋化因子受体3 (CXC chemokine receptor 3, CXCR3)在顺铂诱导骨骼肌萎缩中的作用及机制。将野生型小鼠分为顺铂组和对照组(生理盐水处理)。结果显示，与对照组相比，顺铂组小鼠骨骼肌中CXCR3 mRNA及蛋白表达显著上调，推测CXCR3 在顺铂诱导骨骼肌萎缩模型中可能发挥重要作用。为了探究其作用及可能机制，本研究对CXCR3 基因敲除小鼠及野生型小鼠进行了顺铂注射以诱导骨骼肌萎缩。结果显示，CXCR3 基因敲除非但未改善顺铂诱导的骨骼肌萎缩，反而进一步降低小鼠体重、骨骼肌质量和肌纤维横截面积。进一步分析显示，在顺铂诱导的骨骼肌萎缩模型中，CXCR3 基因敲除显著上调骨骼肌中E3 泛素连接酶的表达，下调生肌相关因子的表达。为了深层次探究CXCR3 基因缺失加重顺铂诱导骨骼肌萎缩的分子机制，本研究对野生型小鼠和CXCR3 基因敲除小鼠萎缩骨骼肌进行了转录组测序分析。结果显示，与野生型小鼠相比，CXCR3 基因敲除小鼠骨骼肌中有14 个基因表达显著上调，12 个基因表达显著下调。基因集富集分析(gene set enrichment analysis, GSEA)结果显示，脂肪酸β-氧化基因集显著富集。实时荧光定量PCR验证结果与转录组测序结果一致。以上结果提示，CXCR3 可能通过上调E3 泛素连接酶、下调生肌调控因子和增强脂肪酸β-氧化相关基因的募集改善顺铂诱导的骨骼肌萎缩。

关键词： 顺铂; 骨骼肌萎缩; CXCR3; 生肌调节因子; 脂肪酸β-氧化途径

CXCR3 counteracts cisplatin-induced muscle atrophy by regulating E3 ubiquitin ligases, myogenic factors, and fatty acid β-oxidation pathways

XU Miao-Miao^1,2, LIU Xiao-Guang³, LU Li-Ming², LI Zhao-Wei^1,*

¹School of Physical Education and Health, Guangzhou University of Chinese Medicine, Guangzhou 510006, China；²Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou 510006, China；³College of Sports and Health, Guangzhou Sport University, Guangzhou 510620, China

Abstract

This study aims to explore the role and mechanism of CXC chemokine receptor 3 (CXCR3) in cisplatin-induced skeletal muscle atrophy. Wild-type mice were divided into two groups: cisplatin group and control group (treated by normal saline). The results showed that, compared to the control group, the expression levels of CXCR3 mRNA and protein were significantly up-regulated in the skeletal muscle of the cisplatin group, suggesting that CXCR3 may play an important role in the model of cisplatin-induced skeletal muscle atrophy. To further investigate its role and potential mechanisms, CXCR3 knockout mice and wild-type mice were treated with cisplatin to induce skeletal muscle atrophy. The results revealed that CXCR3 knockout not only failed to alleviate cisplatin-induced skeletal muscle atrophy, but also further reduced body weight, skeletal muscle mass, and muscle fiber crosssectional area. Further analysis showed that, in the cisplatin-induced muscle atrophy model, CXCR3 knockout significantly up- regulated the expression levels of E3 ubiquitin ligases in skeletal muscle and down-regulated the expression levels of myogenic regulatory factors. To explore the molecular mechanism by which CXCR3 gene deletion exacerbated cisplatin-induced skeletal muscle atrophy, transcriptomic sequencing was performed on the atrophied skeletal muscles of wild-type and CXCR3 knockout mice. The results showed that, compared to wild-type mice, 14 genes were significantly up-regulated and 12 genes were significantly downregulated in the skeletal muscle of CXCR3 knockout mice. Gene set enrichment analysis (GSEA) revealed a significant enrichment of genes related to fatty acid β-oxidation. Quantitative real-time PCR validation results were consistent with the transcriptomic sequencing results. These findings suggest that CXCR3 may counteract cisplatin-induced skeletal muscle atrophy by up-regulating E3 ubiquitin ligases, down-regulating myogenic regulatory factors, and enhancing the recruitment of fatty acid β-oxidation-related genes.

Key words: cisplatin; skeletal muscle atrophy; CXCR3; myogenic regulatory factor; fatty acid β-oxidation pathway

收稿日期：　　录用日期：

通讯作者：李兆伟　　E-mail:

DOI: 10.13294/j.aps.2025.0032

引用本文：

徐苗苗, 刘晓光, 陆丽明, 李兆伟. CXCR3通过调控E3泛素连接酶、生肌因子及脂肪酸β-氧化途径改善顺铂诱导的骨骼肌萎缩[J]. 生理学报 2025; 77 (2): 255-266.

XU Miao-Miao, LIU Xiao-Guang, LU Li-Ming, LI Zhao-Wei. CXCR3 counteracts cisplatin-induced muscle atrophy by regulating E3 ubiquitin ligases, myogenic factors, and fatty acid β-oxidation pathways. Acta Physiol Sin 2025; 77 (2): 255-266 (in Chinese with English abstract).