REDD1 is a major target of testosterone action in preventing dexamethasone-induced muscle loss.
Glucocorticoids are a well-recognized and common cause of muscle atrophy that can be prevented by testosterone. However, the molecular mechanisms underlying such protection have not been described. Thus, the global effects of testosterone on dexamethasone-induced changes in gene expression were evaluated in rat gastrocnemius muscle using DNA microarrays. Gene expression was analyzed after 7-d administration of dexamethasone, dexamethasone plus testosterone, or vehicle. Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone. These data suggest that testosterone blocks dexamethasone-induced changes in expression of REDD1 and other genes that collectively would otherwise down-regulate mTOR activity and hence also down-regulate protein synthesis.
Wu
Yong
Y
Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, 953 Southern Boulevard, Bronx, New York 10468, USA.
Zhao
Weidong
W
Zhao
Jingbo
J
Zhang
Yuanfei
Y
Qin
Weiping
W
Pan
Jiangping
J
Bauman
William A
WA
Blitzer
Robert D
RD
Cardozo
Christopher
C
D000728:Androgens / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000009:adverse effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000009:adverse effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism* / Q000627:therapeutic use; D014157:Transcription Factors
D000728:Androgens; D002352:Carrier Proteins; C000632146:Ddit4 protein, rat; C499526:Eif4ebp1 protein, rat; D005938:Glucocorticoids; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D011944:Receptors, Androgen; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D014157:Transcription Factors; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D038762:Ribosomal Protein S6 Kinases, 70-kDa