Introduction: Differential structural, functional, and metabolic adaptations have been reported in respiratory and limb muscles in animal models of chronic sustained hypoxia, similar to COPD. We sought to elucidate temporal mechanisms that underpin hypoxic remodelling in respiratory muscle. Altered redox modulation is a potential mechanism that supports these adaptations. Method: Adult male C57Bl6/J mice were exposed to one, three and six weeks of sustained hypoxia (FiO2: 0.1) or normoxia (n=8 at each time point). Diaphragm (main respiratory pump muscle) was excised and processed for redox proteomics experiments using fluorescent tags to detect changes in protein carbonyls and free thiols. Mass spectrometry was used to identify redox modified proteins. Spectrophotometric assays were used to measure activities of redox modified metabolic proteins, antioxidants, and activity of the redox-sensitive proteasome. ELISA was used to quantify content of phosphorylated protein synthesis/atrophy signals including phospho(p)-mTOR, p-FOXO3a and p-Akt. Sternohyoid (upper airway dilator), EDL and soleus (hind limb) muscles were analysed for comparative purposes. Results: Hypoxia induces temporal and muscle specific protein oxidation despite an early antioxidant response (p<0.05). Redox remodelling occurs to key metabolic proteins and reaches the level of the cross-bridge. Hypoxia induces temporal and muscle specific activity changes to metabolic proteins. After six weeks of hypoxia, GAPDH, LDH, aconitase, and creatine kinase activities are all decreased in the diaphragm while G3PD activity is increased (P<0.05). Diaphragm and soleus proteasome activities are increased (P<0.05) while no changes were observed in sternohyoid or EDL. Hypoxia induces bi-phasic changes in diaphragm atrophy signalling with p-mTOR increased after one week and p-FOXO3a decreased after six weeks (P<0.05). p-Akt remained unchanged. Discussion: Hypoxia-induced molecular remodelling is muscle specific. Hypoxia per se, contractile activity, molecular composition, and related temporal changes in muscle demands all potentially play a role. The diaphragm, as has been observed in cardiac muscle, appears to favour fatty acids as an energy source in hypoxia. Protein synthesis signalling in the diaphragm is potentially a ‘training effect’ of hypoxia-induced hyperventilation, but atrophy through FOXO3a signalling prevails. Bi-phasic changes in atrophy signalling are unlikely to be growth factor related on the basis of no detectable change in p-Akt content. We hypothesize that redox changes underpin respiratory muscle remodelling in chronic sustained hypoxia.