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Expression of the Muscle Atrophy Factor Muscle Atrophy F-Box Is Suppressed by Testosterone

Center of Excellence for the Medical Consequences of SCI (W.Z., J.P., X.W., Y.W., W.A.B., C.P.C.), James J. Peters Veterans Affairs Medical Center, Bronx, New York 10468; and Department of Medicine (W.A.B., C.P.C.), Mount Sinai School of Medicine, New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Christopher Cardozo, James J. Peters Veterans Affairs Medical Center, Room 1E-02, Bronx, New York 10468. E-mail: chris.cardozo{at}mssm.edu.

The ubiquitin ligase muscle atrophy F-box (MAFbx; also called atrogin-1) is thought to play important roles in muscle loss. Conversely, testosterone reduces atrophy from glucocorticoids or denervation associated with repression of MAFbx. To characterize mechanisms of such repression, the effects of testosterone on MAFbx expression in C2C12 cells were tested. Testosterone reduced MAFbx mRNA levels as well as expression of a reporter gene under the control of 3.1 kb of the human MAFbx promoter. Repression required the androgen receptor (AR) as well as sequences within the first 208 bases upstream of the first codon of the MAFbx gene. This sequence is downstream of known forkhead transcription factor binding sites and testosterone did not alter Forkhead box O 3A phosphorylation. The AR associated with sequences conferring repression in a manner that was stimulated by testosterone and was independent of DNA binding. In gel shift studies, octamer binding transcription factor (Oct)-1 bound two predicted Oct-1 sites within these sequences. Deletion of Oct-1 sites from reporter genes prevented repression by testosterone. Gene knockdown of Oct-1 blocked repression of MAFbx reporter gene activity by testosterone and binding of AR to sequences conferring repression. In conclusion, testosterone represses MAFbx expression via interactions of the AR with Oct-1 that are associated with sequences within the 5' untranslated region of the MAFbx promotor located just upstream of the first codon. This action of testosterone may contribute to beneficial actions of testosterone on muscle.

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