Exercise is a cornerstone of the prevention of no less than thirty-five chronic conditions. Nevertheless, the molecular mechanisms underlying adaptations to exercise and its associated health benefits remain elusive. Here we performed a large-scale integration of the multi-OMIC response to exercise training. A cross-sectional association between DNA-methylation, mRNA or protein levels in human skeletal-muscle and baseline maximal oxygen uptake (VO2max) was conducted. We have also investigated exercise-induced changes in these layers and performed an EWAS meta-analysis of exercise across four training studies, and integrated the results with the ExTraMeta database, and with HIIT-induced proteomic changes from the Gene SMART study. Finally, we investigated the consistency of results between the cross-sectional analysis of VO2max and training-induced changes. At baseline (i.e. pre-training), we showed distinct signature levels marks across the three OMIC layers associated with high levels of VO2max, and genes with the larger effect size associated with skeletal muscle structure and function. Using a powerful meta-analysis for DNA methylation (n=268), and transcriptomics (n=1,100) as well as proteomics data from the Gene SMART cohort (n=148), we investigated exercise-training responses and found only few cpg-sites changed across the methylome, while a myriad of genes and proteins expression levels were significantly associated with exercise response (FDR<0.005).The data integration revealed many significant pathways related to cell structure, metabolism and mitochondrial regulation associated with exercise response. These results were then integrated with a transcriptomic meta-analysis on muscle atrophy and disuse, and multiple pathways including metabolism and mitochondrial-related pathways that were enriched after exercise were depleted after immobilisation. Our analyses uncovered novel genes that might be involved in exercise response such as the BDH1. Finally, several Myod transcription-factors were associated with different methylated regions indicating a potential relationship between TF binding sites and DNA-methylation in the context of exercise.