Molecular Landscape of Sex and Modality-Specific Exercise Adaptation in Human Skeletal Muscle through Large-Scale Multi-OMICs Integration

We investigated the molecular mechanisms of exercise adaptations in human muscle by integrating genome, methylome, transcriptome, and proteome data from over 1,000 participants (2,340 muscle samples). We identified distinctive signatures associated with maximal oxygen consumption (VO 2max ), and multi-omics integration uncovered five key genes as robust exercise markers across layers, with transcription factors functioning as activators, synergizing with DNA methylation to regulate gene expression. Minimal sex-differences were observed, while modality-specific analysis highlighted distinct pathways for aerobic and resistance exercise, contrasting with muscle disuse patterns. Finally, we have created a webtool namely OMAx (https://sarah-voisin.shinyapps.io/OMAEx/) featuring our individual omics and integration analysis. These findings provide a comprehensive multi-omic framework for understanding exercise-induced molecular adaptations, offering insights into muscle health, cardiorespiratory fitness, and their roles in aging and disease prevention.