Multi-omics reveal intricate network of mitochondrial adaptations to training in human skeletal muscle

Abstract Defects in mitochondria have been implicated in multiple diseases and aging; therefore, interventions able to counteract these changes can improve quality of life. Exercise training is a readily accessible and inexpensive therapeutic intervention; however, the complexity of training-induced mitochondrial adaptations in skeletal muscle remains poorly understood. Here, we describe an intricate and previously undemonstrated network of differentially prioritised training-induced adaptations in human skeletal muscle mitochondria. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the increase in mitochondrial content. Moreover, we demonstrate a prioritisation of specific mitochondrial functional protein networks at different stages of the training intervention, including an initial deprioritisation of oxidative phosphorylation (OXPHOS) and a prioritisation of TCA cycle and fatty acid β-oxidation linked mitochondrial respiration. This indicates that enhancing electron flow to OXPHOS may be more important to improve ATP generation in skeletal muscle than increasing the abundance of the OXPHOS machinery. Our research unearths the elaborate and multi-layered nature of the adaptive response to exercise and provides a valuable resource that can be mined to maximise the therapeutic benefits of exercise.