Skeletal muscle hypertrophy and wasting are induced by hypergravity and microgravity, respectively. However, the mechanisms by which gravity change and mechanical stress regulate muscle mass still remain unclear. Although FKBP5 (FK506 binding protein), an immunophilin protein, is related to the signaling in response to glucocorticoid and androgen, the roles of FKBP5 in skeletal muscle remains unknown. We previously reported that hypergravity increases anti-gravity muscle mass, such as soleus muscle, via vestibular system in mice. In the present study, we therefore investigated the influence of gravity change on FKBP5 expression and the roles of this protein in mouse myoblastic C2C12 cells. Bilateral inner vestibules were surgically lesioned (VL) in male C57/BL6 mice, 6 weeks old. After a recovery period for 14 days, the mice were kept in 1 g or 3 g environment for 4 weeks by using a centrifuge. VL blunted the increases in soleus muscle weight induced by hypergravity. We performed comparative comprehensive DNA microarray analysis of soleus muscle among 1g and 3 g with or without VL. The microarray analysis revealed that FKBP5 is included in the genes, whose expressions were enhanced by hypergravity dependently of vestibular system. Stable overexpression of FKBP5 significantly enhanced the levels of myosin heavy chain mRNA in C2C12 cells, compared to empty vector-transfected cells. Moreover, FKBP5 overexpression increased the phosphorylations of Akt and p70 S6 kinase (muscle protein synthesis mTOR pathway). On the other hand, the levels of atrogin-1 and MuRF1 mRNA (muscle protein degradation-related genes) were significantly suppressed in stably FKBP5-transfected C2C12 cells. In conclusion, we first showed that FKBP5 is induced by hypergravity through vestibular system in anti-gravity muscles of mice. Our data suggest that FKBP5 might increase muscle mass through the enhancements of muscle protein synthesis and myotube differentiation as well as an inhibition of muscle protein degradation.