Abstract Body (Do not enter title and authors here): Background: Exercise improves cardiac health and lowers cardiovascular disease (CVD) risk, yet its protective molecular mechanisms remain incompletely understood. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) provides a multi-omic atlas of endurance exercise responses in rat tissues. We performed a sex- and time-resolved integration of heart data to identify key adaptations and their relevance to CVD prevention.
Methods: We applied MEFISTO, a time-aware extension of Multi-Omics Factor Analysis (MOFA2), to integrate longitudinal MoTrPAC multi-omics data—including transcriptomics, epigenomics, proteomics, post-translational modifications, and metabolomics—collected across 1 to 8 weeks of endurance training in male and female rats. Latent factors, which summarize multi-omics features covariation, were used to identify sex-specific molecular responses to endurance exercise. These factors were compared to public CVD datasets to assess shared and divergent molecular signatures.
Results: We identified six latent factors spanning at least three omics layers, including four associated with endurance training. Factors 3, 4, and 5 reflected early, sex-specific adaptations involving energy and fatty acid metabolism. Particularly, Factor 1 captured a progressive, sex-shared signature, strongly correlated with VO2max (r > 0.8, p < 1e–6; Figure 1). This factor reflected a shift from acute metabolic responses to long-term remodeling, with upregulation of ATP metabolism, cardiac morphogenesis, and contractility pathways, supported by epigenetic and post-translational regulation (Figure 2). These findings suggest that endurance exercise enhances mitochondrial efficiency and promotes cardiac tissue maturation. Comparison with human CVD signatures revealed significant inverse enrichment in ischemic heart disease (p < 2e–10), heart failure (p < 2e–3), and cardiac hypertrophy (p < 6e–4). Genes associated with Factor 1 and inversely linked to CVD signatures were enriched for reduced T cell immunity and increased extracellular matrix organization, highlighting a coordinated immunomodulatory and structural adaptation.
Conclusion: Endurance exercise drives sustained molecular remodeling, shifting from early metabolic activation to enhanced mitochondrial efficiency, epigenetic regulation, and cardiac development. Its inverse association with CVD signatures highlights exercise’s protective role through immune modulation and structural remodeling of the heart.