Deciphering the miRNA-mRNA Interaction Network Regulating Aging Skeletal Muscle in Various Exercise Regimens through Comprehensive Bioinformatics Analysis

Abstract

Understanding the impact of different exercise types on skeletal muscle atrophy in older adults is crucial for designing effective strategies to combat age-related muscle loss. This study explores the molecular mechanisms through which resistance exercise (RES) and endurance exercise (END) mitigate skeletal muscle atrophy. By examining microRNA (miRNA) expression profiles from aging skeletal muscle datasets (GSE165632) in the Gene Expression Omnibus (GEO) database, the research aims to uncover exercise-specific miRNA signatures and their associated regulatory pathways. Using the GEO2R analysis tool, researchers identified differentially expressed miRNAs (DEmiRNAs) between RES and END groups. Predicted target genes of these miRNAs were determined through a combination of miRTarBase, micro-T, and TargetScan databases. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, were performed via the DAVID database. Transcription factors were predicted using the ChEA3 database, while protein-protein interaction (PPI) networks were constructed with the STRING database to identify hub genes for further functional enrichment studies. The analysis revealed 30 differentially expressed miRNAs in the RES group and 21 in the END group. In the RES group, key pathways such as FoxO signaling, neurotrophic signaling, insulin resistance, and AMPK were regulated by miRNAs like hsa-miR-574-5p, hsa-miR-34a-5p, and hsa-miR-21-5p. These pathways promote protein synthesis and reduce myocyte apoptosis. In the END group, hub genes were linked to FoxO, TGF-β, MAPK, and cGMP-PKG signaling pathways, regulated by miRNAs such as hsa-miR-194-5p, hsa-miR-146a-5p, and hsa-miR-6831-5p, which enhance mitochondrial function and metabolic regulation. Both exercise types shared common regulatory pathways, including MAPK, TGF-β, and PI3K-Akt, which influence genes like SMAD4 and TRAF6 that are essential for myocyte survival and fibrosis suppression. This study sheds light on the unique and overlapping miRNA-driven regulatory mechanisms behind the effects of RES and END on skeletal muscle atrophy in older adults. Resistance exercise primarily boosts protein synthesis and inhibits apoptosis via pathways like AMPK and p53, while endurance exercise enhances mitochondrial function and energy metabolism through cGMP-PKG signaling. Both exercise modalities converge on critical pathways, providing a scientific basis for developing personalized exercise programs to counteract sarcopenia.

Keywords: Bioinformatics analysis; Endurance exercise (END); Resistance exercise (RES); Sarcopenia; miRNA.