Peripheral Exercise Transcriptomes Do Not Converge on Glutamatergic or Neuroinflammatory Signatures: A Cross-Platform Meta-Analysis

Executive dysfunction following physical overtraining has been linked to glutamatergic dysregulation in the lateral prefrontal cortex (LPFC), but whether this central mechanism is reflected in peripheral gene expression is unknown. This study tested whether peripheral transcriptomic responses to exercise converge on the glutamatergic or neuroinflammatory pathways implicated in LPFC dysfunction. Three publicly available GEO datasets spanning skeletal muscle, whole blood, and circulating neutrophils were analyzed across four exercise groups using limma, with a discovery threshold of nominal p < 0.05 and absolute log2 fold change above 0.5. Differential expression analysis identified 7,311 unique differentially expressed genes (DEGs) across the four contrasts, but overlap between datasets was limited: 7 genes were shared between skeletal muscle and blood, 38 between skeletal muscle and the GSE43856 contrasts, and 90 between blood and the GSE43856 contrasts, with none significant across all three studies. Gene Ontology and KEGG enrichment of the DEG union identified ribonucleoprotein complex biogenesis, ribosome biogenesis, protein folding, and T cell activation as the dominant biological processes; no glutamatergic or neuroinflammatory terms reached significance. Cross-tissue concordance between skeletal muscle and blood was absent (r = 0). Effect sizes among the genes driving the top enriched pathways were dominated by ribosomal proteins, heat shock proteins, and translation initiation factors rather than glutamate receptors or transporters. These findings indicate that peripheral transcriptomic responses to exercise are tissue-specific and dominated by proteostasis, translational, and immune programs rather than glutamatergic signaling. Direct assessment of central nervous system tissue or fluid-based glutamatergic biomarkers may be required to link overtraining-induced fatigue to LPFC dysfunction.