Journal of diabetes investigation · 2026
The role of CXCL10 in high-fat diet-induced skeletal muscle inflammation and atrophy.
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Liyuan An, Hirata Yu, Inoue Tomoya, Sugawara Kenji, Ogawa Wataru
Аннотация
AIMS/INTRODUCTION: Obesity is often accompanied by skeletal muscle atrophy, which aggravates insulin resistance and metabolic dysfunction. Chronic inflammation is implicated in this process, but the molecular mediators linking obesity-induced inflammation to muscle wasting have remained unclear. We investigated the role of the chemokine CXCL10 in skeletal muscle inflammation and atrophy induced by a high-fat diet (HFD).
MATERIALS AND METHODS: Male C57BL/6J mice were fed an HFD or normal diet for 2 weeks and received either neutralizing antibodies to CXCL10 or control immunoglobulin G. Muscle morphology, macrophage infiltration, and gene expression were examined by histology, immunohistochemistry, reverse transcription-quantitative polymerase chain reaction analysis, and RNA sequencing. Cultured C2C12 myotubes were also treated with recombinant CXCL10 or lipopolysaccharide (LPS), with or without antibodies to CXCL10, for assessment of direct effects on myotube atrophy.
RESULTS: HFD feeding upregulated Cxcl10 expression in skeletal muscle. It also induced fiber atrophy, macrophage infiltration, and increased expression of individual inflammation- or proteolysis-related genes in muscle, with these effects being attenuated by CXCL10 neutralization. Transcriptomic analysis further revealed a broad reversal of HFD-induced changes in gene expression related to protein catabolism and myofiber structure by anti-CXCL10 administration. Both CXCL10 and LPS reduced myotube diameter and increased expression of catabolism- or inflammation-related genes in cultured C2C12 myotubes, whereas CXCL10 blockade prevented these effects of LPS.
CONCLUSIONS: CXCL10 mediates HFD-induced skeletal muscle atrophy by promoting inflammation and proteolysis. CXCL10 neutralization mitigates such muscle loss and may represent a novel therapeutic strategy to preserve skeletal muscle mass under metabolic stress.
MATERIALS AND METHODS: Male C57BL/6J mice were fed an HFD or normal diet for 2 weeks and received either neutralizing antibodies to CXCL10 or control immunoglobulin G. Muscle morphology, macrophage infiltration, and gene expression were examined by histology, immunohistochemistry, reverse transcription-quantitative polymerase chain reaction analysis, and RNA sequencing. Cultured C2C12 myotubes were also treated with recombinant CXCL10 or lipopolysaccharide (LPS), with or without antibodies to CXCL10, for assessment of direct effects on myotube atrophy.
RESULTS: HFD feeding upregulated Cxcl10 expression in skeletal muscle. It also induced fiber atrophy, macrophage infiltration, and increased expression of individual inflammation- or proteolysis-related genes in muscle, with these effects being attenuated by CXCL10 neutralization. Transcriptomic analysis further revealed a broad reversal of HFD-induced changes in gene expression related to protein catabolism and myofiber structure by anti-CXCL10 administration. Both CXCL10 and LPS reduced myotube diameter and increased expression of catabolism- or inflammation-related genes in cultured C2C12 myotubes, whereas CXCL10 blockade prevented these effects of LPS.
CONCLUSIONS: CXCL10 mediates HFD-induced skeletal muscle atrophy by promoting inflammation and proteolysis. CXCL10 neutralization mitigates such muscle loss and may represent a novel therapeutic strategy to preserve skeletal muscle mass under metabolic stress.