Aerobic exercise is associated with alleviation of skeletal muscle atrophy in CT26 tumor-bearing mice: insights from transcriptomic and weighted gene co-expression network analyses

BACKGROUND: Cancer-associated skeletal muscle atrophy is a major manifestation of cachexia and is closely associated with inflammation, metabolic disturbance, and muscle structural deterioration. Aerobic exercise has been considered a promising non-pharmacological intervention, but its molecular mechanisms in tumor-associated muscle wasting remain incompletely understood. This study aimed to investigate transcriptomic changes associated with the effects of aerobic exercise on skeletal muscle wasting-related alterations in CT26 tumor-bearing mice and to identify candidate hub genes using weighted gene co-expression network analysis. METHODS: Eight-week-old specific pathogen-free male BALB/c mice were randomly assigned to four groups: control, exercise, tumor-bearing, and tumor-bearing plus exercise. CT26 cells were subcutaneously inoculated to establish the tumor-bearing model. Mice in the exercise groups underwent treadmill-based aerobic training for 4 weeks. Gastrocnemius muscles were collected for hematoxylin-eosin staining and transcriptome sequencing. Differentially expressed genes were identified, followed by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Weighted gene co-expression network analysis was further performed to identify phenotype-related modules and candidate hub genes. RESULTS: Tumor-bearing mice showed reduced gastrocnemius wet weight and histological abnormalities characterized by disorganized muscle fiber arrangement and structural damage. Compared with the tumor-bearing group, the tumor-bearing plus exercise group exhibited a significant increase in gastrocnemius wet weight alongside a qualitative trend toward histomorphological recovery. Transcriptomic analysis showed that tumor burden upregulated pathways related to inflammation and protein degradation, while downregulating pathways associated with energy metabolism and maintenance of muscle structure. Aerobic exercise was associated with partial reversal of these transcriptional trends. Enrichment analyses indicated that the differentially expressed genes were mainly involved in the PI3K-Akt, NF-kappa B, and IL-17 signaling pathways. Weighted gene co-expression network analysis identified an inflammation-related module closely associated with the tumor-bearing phenotype, in which S100a8 was recognized as a candidate hub gene. CONCLUSIONS: Aerobic exercise was associated with a significant improvement in gastrocnemius wet weight and a mitigating trend in histomorphological abnormalities in CT26 tumor-bearing mice, which may be associated with remodeling of inflammation- and metabolism-related transcriptional networks. S100a8 may represent a candidate hub gene associated with this process, although further functional validation is required.