Omics-driven investigation of the biology underlying intrinsic submaximal working capacity and its trainability

Submaximal exercise capacity is an indicator of cardiorespiratory fitness with clinical and public health implications. Submaximal exercise capacity and its response to exercise programs are characterized by heritability levels of about 40%. Using physical working capacity (power output) at a heart rate of 150 beats/min (PWC150) as an indicator of submaximal exercise capacity in subjects of the HERITAGE Family Study, we have undertaken multi-omics and in silico explorations of the underlying biology of PWC150 and its response to 20 wk of endurance training. Our goal was to illuminate the biological processes and identify panels of genes associated with human variability in intrinsic PWC150 (iPWC150) and its trainability (dPWC150). Our bioinformatics approach was based on a combination of genome-wide association, skeletal muscle gene expression, and plasma proteomics and metabolomics experiments. Genes, proteins, and metabolites showing significant associations with iPWC150 or dPWC150 were further queried for the enrichment of biological pathways. We compared genotype-phenotype associations of emerging candidate genes with reported functional consequences of gene knockouts in mouse models. We investigated the associations between DNA variants and multiple muscle and cardiovascular phenotypes measured in HERITAGE subjects. Two panels of prioritized genes of biological relevance to iPWC150 (13 genes) and dPWC150 (6 genes) were identified, supporting the hypothesis that genes and pathways associated with iPWC150 are different from those underlying dPWC150. Finally, the functions of these genes and pathways suggested that human variation in submaximal exercise capacity is mainly driven by skeletal muscle morphology and metabolism and red blood cell oxygen-carrying capacity.