Muscle atrophy is a multifactorial process common in different catabolic conditions including disuse and aging. Muscle atrophy in most conditions is characterized not only by a change in muscle mass, i.e. a change in muscle quantity, but also by a change of the intrinsic capacity of muscle to develop force, i.e. a change in muscle quality, weakness depending on both phenomena. However, the underlying mechanisms widely vary among different conditions and even through disuse models. We analyzed three human disuse models: Bed Rest of 8, 24 and 35 days (BR), Unilateral Lower Limb Suspension (ULLS) of 21 days and space flight (SF) of 6 months. Loss of mass occurred at whole muscle level and at single fiber level in all models to a similar extent. CSA of single muscle fibres was 20-30% lower following 35 days of BR, 23% lower following 3 weeks of ULLS and 23-45% lower following 6 months of SF. In all conditions, a significant loss of specific force of individual muscle fibres was observed. The latter phenomenon was accounted for in BR and ULLS by a disproportionate loss of myosin content compared to CSA, i.e. by a lower myosin concentration and a lower number of potential acto-myosin interactions within individual muscle fibres. Interestingly, in all model, proteomic analysis indicated a down-regulation of many other myofibrillar proteins besides a loss of myosin even at early times of disuse when muscle atrophy had not developed yet, i.e. after 8 days of BR. It appears that both muscle quantity and quality are affected by disuse. Notwithstanding the similar adaptations observed in muscle mass, function and protein pattern, the underlying molecular mechanisms were somewhat different. Following BR (24 days) and ULLS (21 days) no activation of the ubiquitin proteasome system (UPS) was observed, i.e. no changes of MuRF-1 and Atrogin 1, two major markers of the UPS. On the contrary, following 6 months SF UPS was activated. The present data did not support a significant contribution of the UPS at least in the progression of muscle atrophy at late stages of BR and ULLS, whereas in SF the UPS system role could be more relevant as it could remain active for long time. Post BR and post SF autophagy was activated, whereas post ULLS it was not. On the contrary, the Akt/mTOR pathway, which control protein synthesis, was downregulated following ULLS, but not following BR (no data post SF). Interestingly, in humans, a decrease in protein synthesis has been suggested to be the major cause of muscle mass loss. The molecular adaptations observed could be triggered by mitochondrial dysfunction and/or redox unbalance. Proteomic analysis showed complex adaptations of the metabolic enzymes content that collectively indicate a general derangement of energy metabolism in BR, ULLS and SF. Interestingly, in a mouse model of disuse (hind-limb unloading) similar metabolic impairment was observed and a metabolic program was shown to cause muscle atrophy. Such metabolic impairment was found to be based on PGC-1α down-regulation and/or mitochondrial dysfunction. PGC-1α is a master controller of mitochondrial biogenesis. It was down-regulated in BR (after 8, 10, 21 and 24 days) but not in ULLS. Moreover, in BR the metabolic impairment was supported by the alteration of mitochondrial dynamic, namely by the down-regulation of mitochondrial fusion and the up-regulation of mitochondrial fission. On the contrary, in SF PGC-1 α was up-regulated. The latter finding could be due to the impact of countermeasures astronauts had to perform to try to limit loss of muscle mass. Collectively the data suggest that in humans PGC-1α contribution to trigger muscle wasting is complex and variable through disuse models. Redox unbalance is considered an important factor involved in muscular atrophy. We observed a different role of oxidative stress in BR and ULLS. In fact, in BR all anti-oxidant defence systems were downregulated in an early stage of disuse (8 days), NRF2, a master controller of antioxidant protein expression, was up-regulated and protein carbonylation occurred following 35 days suggesting that oxidative stress developed. In ULLS antioxidant defence systems were up-regulated, NRF2 was unchanged and no protein carbonylation occurred after 21 days. The latter observations indicate an effective cellular response to a possible redox imbalance and do not support a major role of oxidative stress in ULLS. The alterations observed suggested that the atrophic stimulus translates in different adaptations in BR, ULLS and SF models although the final outcome, i.e.loss of mass and myosin content, is similar. Since BR, ULLS and SF reproduce conditions of clinical interest, the comprehension of the mechanisms responsible for the specific muscles adaptations could be relevant to designing specific countermeasures or rehabilitation protocols.