FOXO1 is a transcription factor known to reduce muscle size, and to upregulate MAFbx and MuRF1 selleck bio and the protein synthesis inhibitor 4EBP1. Nandrolone induced reductions in FOXO1 at 35 but not 7 days agree well with the prior observation that nandrolone reduced expression of MAFbx and MuRF1 at 35 but not 7 days. The find ings suggest that downregulation of FOXO1 represents a likely mechanism by which nandrolone slows denerva tion atrophy. To our knowledge, neither RCAN2 nor calcineurin have been previously suggested to be involved in nandro lone action or denervation atrophy. Calcineurin is a cal cium Inhibitors,Modulators,Libraries calmodulin dependent dual specificity phosphatase which promotes the slow twitch endurance muscle fiber type. At 35 days, nandrolone reduced expression of RCAN2, and RCAN2 levels were inversely correlated with the size of denervated gastrocnemius.

Nandrolone also altered the expression of a regulatory subunit of cal cineurin, calcineurin B, type Inhibitors,Modulators,Libraries 1. Of interest, in studies of calcineurin function in the pathogenesis of cardiac hyper trophy, calcineurin activity has been shown to be reduced by MAFbx, FOXO1 or FOXO3A, and to be directly linked to myocardiocyte size. The role of calci neurin in hypertrophy of normal skeletal muscle hyper trophy, Brefeldin_A or spontaneous recovery from muscle atrophy, is controversial. Its roles in denervated mus cle, or androgen action, are unknown. We are now inves tigating the relationship between nandrolone action and calcineurin in atrophied skeletal muscle.

Increased expression of inhibitors of mTOR, such as REDD1 and REDD2, have Inhibitors,Modulators,Libraries been linked to decreases in cell size and protein synthesis and have been suggested to promote muscle atrophy. mTOR is a master regulator of protein synthesis and is necessary for muscle hypertrophy and recovery of mus cle size after muscle atrophy. Upregulation Inhibitors,Modulators,Libraries of mTOR inhibitors has been described during muscle atrophy caused by glucocorticoids or alcohol inges tion and has been implicated in mTOR inhibition due to glucocorticoids in cultured myoblasts. Of interest, testosterone prevented upregulation of REDD1 in dexamethasone treated rats and cultured myoblasts and normalized mTOR activity in cultured cells exposed to dexamethasone. Consistent with these findings, in denervated muscle, nandrolone reduced REDD2 mRNA and protein at 35 but not 7 days, suggesting that reduction in expression of this protein, and subsequent increases in mTOR activity, may represent one mechan ism by which nandrolone slows denervation atrophy. Other genes upregulated selleck kinase inhibitor at 35 days by nandrolone include Wnt signaling molecules and ApoD. Wnt signaling appears to be important to muscle hypertrophy.