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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

Received: 　　Accepted:

Corresponding author: 李兆伟　　E-mail:

DOI: 10.13294/j.aps.2025.0032

Citing This Article：

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).