Exercise training response heterogeneity: physiological and molecular insights

The overall beneficial effects of exercise are well studied, but why some people do not respond favourably to exercise is less understood. The National Institutes of Health Common Fund has recently launched the large-scale discovery project ‘Molecular Transducers of Physical Activity in Humans’ to examine the physiological and molecular (i.e. genetic, epigenetic, lipidomic, metabolomic, proteomic, etc.) responses to exercise training. A nationwide, multicentre clinical trial such as this one also provides a unique opportunity to robustly investigate the non-response to exercise in thousands of individuals that have undergone supervised aerobic- and resistance-based exercise training interventions. The term ‘non-responder’ is used here to address the lack of a response (to an exercise intervention) in an outcome specified a priori. Cardiorespiratory fitness (\( \dot{V}{\mathrm{O}}_{2\mathrm{peak}} \)) as an exercise response variable was recently reviewed; thus, this review focuses on metabolic aspects of the non-response to exercise training. Integrated -omics platforms are discussed as an approach to disentangle the complicated relationships between endogenous and exogenous factors that drive the lack of a response to exercise in some individuals. Harnessing the power of combined -omics platforms with deep clinical phenotyping of human study participants will advance the field of exercise metabolism and shift the paradigm, allowing exercise interventions to be targeted at those most likely to benefit and identifying novel approaches to treat those who do not.