Our data revealed a significant up-regulation in MuRF-1 and Atrogin-1 within the initial days of immobility, with no difference between young and aged muscle. Similar results have recently been observed after 48 h and 72 h of unloading in young human individuals, which could suggest a role for the ubiquitin-proteasome pathway in the initiation of human skeletal muscle atrophy. The fact that we observed more modest changes compared to previous animal reports may reflect that more Butenafine hydrochloride drastic and/or systemic wasting models were used in these animal studies compared to human immobilization models. Notably, the present data revealed that expression levels of Atrogin-1 and MuRF-1 returned to basal levels after 14 days of immobility in young individuals and was further down-regulated in old individuals, along with a smaller decrease in muscle fiber area. These Folinic acid calcium salt pentahydrate findings may indicate that in human skeletal muscle important for the initial and rapid loss of muscle mass with disuse but may not be important for a more prolonged atrophy response. Notably, a similar timecourse of MuRF-1 and Atrogin-1 expression levels has been demonstrated in the rat model after denervation and spinal cord injury. A transient rise in signaling markers of protein degradation does, however, not exclude a simultaneous down-regulation of protein synthesis with immobilization which has been demonstrated to occur in young individuals. In line with these results, as well as previous data shown by Booth and coworkers in a rat model, a decline was observed in phosphorylated Akt and phosphorylated ribosomal protein S6 in the initial phase of immobility in the present study. In addition to being a central regulator of muscle protein synthesis and muscle hypertrophy the IGF-1/Akt signaling pathway has been proposed to be a potent suppressor of myofibrillar proteolysis and atrophy related ubiquitin ligases, respectively. In speculative terms, the present findings of an age-specific pattern in Akt and ribosomal protein S6 phosphorylation suggests that immobility leads to reduced protein synthesis in young skeletal muscle, in line with previous findings. In contrast, the – relative to young – higher Akt phosphorylation in elderly in combination with an early up-regulation of MGF and IGF-1Ea expression is potentially contributing to the attenuated atrophy response in aging skeletal muscle observed in the present study. In support of these findings, the expression of molecular markers for anabolic signaling and elevated protein synthesis rate either remained unchanged or increased in 24 and 27 months old sarcopenic rats compared to young animals. Although a coordinated regulation of the ubiquitin-proteasome and the autophagy-lysosome pathways has been shown to exist in mice, the present study did not demonstrate an increase in expression levels of ATG4, GABARAPL or FoxO3 mRNAs. However, we did see a trend towards an increase in LC3B II/I protein ratio selectively in young muscle after 1 d and 4 d of immobility, which suggests that the autophagic process was initiated at least in the young myofibers and thus, crosstalk between the ubiquitin-proteasome and the autophagy-lysosome pathways may also exist in the human model. However, more detailed studies investigating both upstream and downstream regulators of the autophagic and proteolytic processes in humans are needed to elucidate these signaling pathways. Further, the present data revealed that disuse of skeletal muscle resulted in a marked down-regulation of genes involved in oxidative metabolism.