Deciphering V̇_O: limits of the genetic approach

Maximal oxygen consumption (V̇_O) denotes the upper limit of aerobic energy flux through the cascade of oxygen transfer from the environment to tissue mitochondria, essentially to skeletal muscle mitochondria during intense exercise. A high V̇_O is a key component for athletic success in human and animal endurance sports. From a public health perspective, a high V̇_O is a validated negative predictor for cardiovascular disease and all-cause mortality. V̇_O varies by more than twofold between sedentary subjects and shows a heritability value greater than 50%. Likewise, the capacity for an individual's V̇_O to be increased with exercise training (i.e. its trainability) varies massively between subjects, independent of each subject's V̇_O in the absence of training (i.e. their sedentary V̇_O), and with a similarly high heritability. Athletic as well as public health interests have prompted a search for the genetic profile of sedentary V̇_O and of trainability. Candidate-gene studies, gene-expression studies and genome-wide-association studies (GWAS) have not been able to identify a genetic signature that distinguishes subjects or athletes with a favorable V̇_O phenotype or a high trainability from controls. Here, I propose that multigenetic phenotypes such as V̇_O are emergent properties of multiple underlying transcriptomic networks modified by epistasis, the epigenome and the epitranscriptome. The genetic approach is thus considered to be necessary but insufficient for furthering our understanding of multigenetic higher-level functions.