Specifically, our results demonstrated age-specific differences in the modulation of PGC1a and PGC-1b, with a delayed and smaller response in old muscle compared to that of young individuals. These findings support the hypothesis that the down-regulation of PGC-1a and PGC-1b could be important determinants for the initiation of human skeletal muscle atrophy, as also observed in rodents. Although only minor transcriptional changes of FoxO were noted in the present study, we found a rapid increase in atrogenes downstream of FoxO. However, as protein levels of FoxO were not determined, it is not possible to exclude that high levels of FoxO in the cell and the nucleus will feedback upon the FoxO signaling it self. If so, the present finding of reduced FoxO after 4 days could reflect a feedback phenomenon. Another topic of debate has been the role of apoptosis in human skeletal muscle atrophy and sarcopenia. There are a significant amount of data indicating an important role for apoptosis in the development of muscle atrophy observed with aging in animal models, whereas human data have been more inconsistent. Notably, despite an increase in TUNELpositive nuclei was observed primarily in aging muscle after immobility, there were limited signs of specific cellular TUNEL-positive myonuclei in young as well as old muscle, in contrast to previous findings in the murine model. The TUNEL-positive nuclei observed in the present study were primarily localized in the interstitial space between muscle cells and the cellular origin and were neither macrophages, endothelial cells nor muscle satellite cells. Thus myofiber as well as muscle satellite cells apoptosis seems not to play a key role for the initiation of human disuse-muscle atrophy in agreement with recent mice studies. In conclusion, the present findings collectively demonstrate that a number of signaling pathways related to both muscle atrophy and muscle hypertrophy are activated in the initial phase of disuse along with a rapid atrophy response in skeletal muscle of both young and old individuals. Importantly, activation of the ubiquitin-proteasome pathway was observed along with a down regulation of PGC-1a and PGC-1b during the first 1�C2 days of disuse, suggesting that proteolysis may play an important role in the initiation of human disuse atrophy in both young and old muscle. These changes were accompanied by rapid decreases in phosphorylated Akt and phosphorylated ribosomal protein S6 selectively in young muscle. In contrary, aged muscle selectively Tulathromycin B showed an elevated Akt phosphorylation and up-regulation of IGF-1Ea and MGF in combination with a decrease in Atrogin-1 and MuRF-1 mRNA expression levels and a less marked atrophy response in the later phase of disuse. Although several fundamental mechanistic questions in regards to muscle loss remains to be answered, the present data provide novel insights into the Folinic acid calcium salt pentahydrate molecular regulation of human skeletal muscle disuse-atrophy and its modulation by aging. Our findings indicate that the initiation and regulation of human skeletal muscle atrophy is age dependent and involves a number of independent signaling pathways. These findings may be important for the identification of biomarkers and future therapeutic intervention paradigms that can be used to counteract human skeletal muscle atrophy in relation to aging and disuse. Recent progress in unraveling the biology of MM, particularly the intracellular signaling pathways and the interactions with the bone marrow microenvironment, has resulted in development of novel targeted therapy.