Predicting the responsiveness to regular exercise is a topic of great relevance due to its potential role in personalized exercise medicine applications. The present review focuses on cardiorespiratory fitness (commonly measured by maximal oxygen uptake, Symbol), a trait with wide-ranging impact on health and performance indicators. Gains in Symbol demonstrate large inter-individual variation even in response to standardized exercise training programmes. The estimated Symbol heritability of 47% suggests that genomic-based predictors alone are insufficient to account for the total trainability variance. Candidate gene and genome-wide linkage studies have not significantly contributed to our understanding of the molecular basis of trainability. A genome-wide association study suggested that Symbol trainability is influenced by multiple genes of small effects, but these findings still await rigorous replication. Valuable evidence, however, has been obtained by combining skeletal muscle transcript abundance profiles with common DNA variants for the prediction of the Symbol response to exercise training. Although the physiological determinants of Symbol measured at a given time are largely enunciated, what is poorly understood are the details of tissue-specific molecular mechanisms that limit Symbol and related signalling pathways in response to exercise training. Bioinformatics explorations based on thousands of variants have been used to interrogate pathways and systems instead of single variants and genes, and the main findings, along with those from exercise experimental studies, have been summarized here in a working model of Symbol trainability.
A working model of the two basic components of research focused on the trainability of Symbol. The first component aims at identifying biomarkers and predictors of variation in responsiveness. The second targets technologies, research strategies and designs that have the potential to shed light on the physiology, pathways, systems, signalling, and small and large molecular transducers of adaptability to regular exercise with an emphasis on individual differences. See text for more details.