Deciphering (V) over dotO2,max: limits of the genetic approach

Maximal oxygen consumption ((V) over dot(O2,max)) 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 (V) over dot(O2,max )is a key component for athletic success in human and animal endurance sports. From a public health perspective, a high (V) over dot(O2,max) is a validated negative predictor for cardiovascular disease and all-cause mortality. (V) over dot(O2,max) varies by more than twofold between sedentary subjects and shows a heritability value greater than 50%. Likewise, the capacity for an individual's (V) over dot(O2,max) to be increased with exercise training (i.e. its trainability) varies massively between subjects, independent of each subject's (V) over dot(O2,max) in the absence of training (i.e. their sedentary (V) over dot(O2,max)), and with a similarly high heritability. Athletic as well as public health interests have prompted a search for the genetic profile of sedentary (V) over dot(O2,max) 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 (V) over dot(O2,max) phenotype or a high trainability from controls. Here, I propose that multigenetic phenotypes such as (V) over dot(O2,max) 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.