Transcriptomic Signatures of Exercise-Modality Responses in Aged Human Skeletal Muscle

Objective: Exercise training helps preserve skeletal muscle health during aging. However, the molecular responses to different exercise modalities in older adults remain unclear. This study reanalyzed human skeletal muscle transcriptomes to compare signatures associated with combined training, resistance training, and high-intensity interval training. Method: We analyzed the older adult subset of GSE97084. This subset included 46 skeletal muscle RNA-seq samples from 23 participants with paired biopsies before and after training. The dataset included seven paired participants in the combined group, eight in the resistance training (RT) group, and eight in the high-intensity interval training (HIIT) group. We performed paired differential expression analysis, GO/KEGG enrichment analysis, GSEA, WGCNA, PPI analysis, regulatory network analysis, and transcriptome-inferred microenvironment signature analysis. Results: The within-modality paired comparisons identified 264 DEGs in the combined group, 297 DEGs in the RT group, and 1098 DEGs in the HIIT group. A total of 62 DEGs were shared across all three modalities. Combined training was mainly linked to extracellular matrix (ECM) organization, vascular regulation, and mitochondrial oxidative metabolism. RT showed prominent collagen, ECM, integrin, focal adhesion, and structural remodeling signatures. HIIT showed the broadest DEG profile under the current threshold. HIIT was characterized by vascular endothelial, angiogenic, ECM/adhesion, oxidative phosphorylation, and immune-related microenvironment signatures. WGCNA and PPI analyses identified candidate hub gene patterns. ECM and basement membrane genes were more prominent after combined training and RT. Vascular endothelial genes were more evident after HIIT. Regulatory network analysis highlighted miR-29 family members as database-supported candidate regulators of ECM-related hub genes. Transcriptome-inferred microenvironment analysis suggested increased endothelial-related signatures across all modalities. This analysis also suggested increased fibroblast/stromal signatures after RT and HIIT and increased macrophage-related signatures after HIIT. Conclusions: Different exercise modalities were associated with partially overlapping but distinct transcriptomic signatures in aged human skeletal muscle. Combined training and RT were mainly related to ECM, stromal, and structural remodeling signatures. HIIT showed broader vascular endothelial and microenvironment-related signatures. These findings should be interpreted as exploratory because this reanalysis used a modest older adult subset from a single public bulk RNA-seq dataset and lacked an independent validation cohort. Larger studies and complementary experimental validation are needed before drawing definitive conclusions about exercise-modality-specific responses in aged human skeletal muscle.