Among coregulators with less dramatic changes in expression between 7 and 35 days, selleck chem inhibitor several are known to regulate transcriptional activities of the AR, CREBBP, Tgif, Ctdsp1 and NRIP1. Interactions between the AR and other transcription factors have been reported for GR, Ets1, Oct1, NFkB, FOXO1 and AP1. Many transcription factors demonstrated altered expression between 7 and 35 days. Although interactions of these transcription factors with the AR have not been reported, it remains possible that these occur, and that changes in their expression may be linked to some of the time dependent effects of nandrolone. Other mechanisms may also be involved in, or be cri tical to, time dependent effects of nandrolone on gene expression.

These may include changes in phosphoryla tion status of transcriptional regulators, or non genomic effects of nandrolone mediated through interactions with kinases, G proteins, or other intracellular signaling molecules. For example, it has been demonstrated that transcriptional activity of PGC 1a is determined by activity of the kinases AMPK and p38 MAPK. Thus, the findings suggest several possible mechan isms that may explain the time dependent effects of nandrolone on gene expression in denervated muscle. Future investigations focused on more detailed time course studies, interactions of proteins encoded by these regulatory genes with the AR, and their effects on nan drolone target genes such as FOXO1 or MAFbx, hold the promise of identifying the specific molecular interac tions by which nandrolone exerts such profoundly dif ferent actions over time.

Comparison with other studies of androgen actions in atrophied muscle An interesting consideration is that the effects of nan drolone to slow atrophy of denervated gastrocnemius are much greater than its effects to increase the mass of normal rat muscles, including gastrocnemius, but that both of these actions of nandrolone are consider ably smaller than the dramatic effect of androgens to increase the size of the rat levator ani muscle. It is possible that similar mechanisms determine androgen responsiveness of these normal and denervated muscles. It is also possible that the marked changes in expression of key regulatory molecules that occurs with time after denervation play important roles in determining androgen sensitivity of denervated muscle that are dis tinct from those that specify the androgen responses of normal muscle and the levator ani.

In either case, the time dependent differences in nan drolone effects on denervated muscle appear to be one manifestation of a more general influence of the physio logical state Carfilzomib of skeletal muscle on responses to andro gens. For example, genes regulated by nandrolone at 7 or 35 days differed from those regulated by androgens in other genomic studies.