Multi-Omics Identification of Fos as a Central Regulator in Skeletal Muscle Adaptation to Long-Term Aerobic Exercise

Skeletal muscle health and function are closely linked to long-term aerobic exercise, particularly in enhancing muscle metabolism and regulating gene expression. Regular endurance training can significantly ameliorate metabolic dysfunction and prevent chronic diseases. However, the precise molecular mechanisms underlying skeletal muscle adaptations to long-term aerobic exercise require further clarification. To address this, we integrated transcriptomic and single-cell omics datasets from multiple long-term aerobic exercise models retrieved from the GEO database. After merging and batch correction, differential expression analysis identified 204 DEGs, including 110 upregulated and 94 downregulated genes. Key feature genes were screened using Lasso regression, SVM-RFE, and Random Forest machine learning algorithms, validated by RT-qPCR, and refined through PPI network analysis. Among them, <i>Fos</i> and <i>Tnfrsf12a</i> were significantly downregulated following long-term aerobic exercise. Notably, <i>Fos</i> exhibited a more pronounced decrease than <i>Tnfrsf12a</i>, and was strongly associated with inflammation and muscle regeneration. PPI network analysis indicated that <i>Fos</i> interacted with genes such as <i>Casp3</i>, <i>Egr1</i>, <i>Aft3, Hspa5</i>, <i>Src</i>, and <i>Igf2</i>. GO, KEGG, and GSEA enrichment analyses revealed that <i>Fos</i> is involved in skeletal muscle differentiation, tissue remodeling, and the NF-κB inflammatory pathway. ssGSEA analysis further showed that samples with low <i>Fos</i> expression had significantly elevated Th1/Th2 and Treg cell infiltration. Single-cell analysis confirmed preferential <i>Fos</i> expression in muscle fiber/adipocyte progenitors, satellite cells, and tenocytes, all critical for myogenesis. In summary, our findings suggest that long-term aerobic exercise downregulates <i>Fos</i>, potentially alleviating inflammation and enhancing satellite cell-mediated muscle regeneration. <i>Fos</i> may serve as a central regulator of skeletal muscle remodeling during long-term aerobic exercise.