Although oxidative stress is widely recognized to play a pivotal role in most conditions of muscle wasting, several other mechanisms could be involved among which an impairment of muscle capacity to utilize glucose and produce energy. PGC-1a, a major controller of mitochondria biogenesis, was down regulated in several models of muscle atrophy and its over-expression counteracted muscle wasting in denervation and fasting. Branched chain amino acid administration in mice prevented aging induced sarcopenia and suggested a possible interplay between impaired metabolism and oxidative stress in its pathogenesis. In disuse atrophy, whereas the causal role of oxidative stress has been studied in detail, limited information is available on the possible role of metabolic impairment. We have recently addressed such issue employing a proteomic and gene expression approach. In atrophic solues muscle of hindlimb unloaded (HU) mice, both an impairment of antioxidant defense systems and an overall down-regulation of enzymes involved in energy metabolism occurred. Moreover, antioxidant treatment up-regulated antioxidant defense systems, but did not prevent muscle atrophy and metabolic impairment. Human vastus lateralis muscle following 35 days bed rest showed an impairment of antioxidant defense systems and a metabolic derangement confirmed by the down-regulation of PGC-1a and up-regulation of SREBP, a master controller of lipid synthesis. In an attempt to clarify the mechanisms underlying disuse atrophy and the interplay between oxidative stress and impaired metabolisms, we studied the time course of muscle atrophy and of changes in muscle proteome and gene expression in HU mice.