The time course of the adaptations of human muscle proteome to bed rest and the underlying mechanisms

•  It is still debated whether an imbalance between production and removal of reactive oxygen species is a major trigger of disuse skeletal muscle atrophy in human limb muscles and what the underlying mechanisms are. •  In the bed rest model of human disuse, redox imbalance, impairment of antioxidant defence systems and metabolic derangement occurred early, before vastus lateralis muscle atrophy developed, and persisted through 35 days of bed rest. •  Down‐regulation of PGC‐1α, a master controller of muscle metabolism, and up‐regulation of SREBP‐1, a master controller of lipid synthesis, are likely to have triggered disuse adaptations through mitochondrial dysfunction, whereas AMP kinase, an energy sensor pathway, was unaltered. •  The present and previous results on the same subjects suggest a causal link between muscle atrophy, impaired skeletal muscle metabolism, impaired whole body oxidative metabolism, and insulin sensitivity and moderate inflammation, which are major risk factors of physical inactivity related diseases.