The current scientific landscape lacks comprehensive integrative studies that thoroughly investigate the molecular mechanisms governing exercise adaptations. Our primary aim was to address this gap by conducting a detailed examination of the multi-OMIC response to exercise training.
Initially, we carried out a cross-sectional analysis, establishing connections between DNA methylation, transcriptomic, and proteomics in human skeletal muscle with baseline maximal oxygen uptake (VO2max). This involved conducting meta-analyses, including an epigenome-wide association study (EWAS – n=702), a transcriptome-wide association study (TWAS – n=353), and a proteome-wide association study (PWAS- n=160) of VO2max, followed by an integrated analysis of these layers. Our EWAS reveled 9822 differentially methylated positions (DMPs), 162 transcripts and 351 proteins to be associated with VO2max levels. Based on the DMPs 15 transcription factors were identified to be derived from those regions. Of the 162 significant transcripts associated with VO2max 157 where derived from genomic regions containing at least one TFBS for the enriched 20 TFs derived from our hyper- and hypo-DMRs suggesting an indirect feedback loop between DNA methylation and transcription. Multi-contrast gene set enrichment analysis identified 210 pathways associated with VO2max in all three layers. Inverse relationship between methylation and mRNA and proteins for pathways related to Mitochondrial function where a decrease in DNA methylation was observed with a concomitant increase in mRNA and protein expression.
Subsequently, we delved into exercise-induced changes in the methylome, transcriptome, and proteome. An EWAS meta-analysis (n=602) of exercise was conducted, and the findings were integrated with the ExTraMeta database. Additionally, high-intensity interval training (HIIT)-induced proteomic changes from a PWAS meta-analysis (n=160) were incorporated. The EWAS analysis of exercise-induced training adaptations was further divided based on exercise modalities (aerobic and resistance training) to highlight distinctions in molecular responses with different training approaches in the epigenetic level. Interestingly, distinctive signature levels across the three OMIC layers were associated with exercise training, with genes displaying larger effect sizes linked to skeletal muscle structure and function.