Expression of androgen receptor target genes in skeletal muscle.
We aimed to determine the mechanisms of the anabolic actions of androgens in skeletal muscle by investigating potential androgen receptor (AR)-regulated genes in in vitro and in vivo models. The expression of the myogenic regulatory factor myogenin was significantly decreased in skeletal muscle from testosterone-treated orchidectomized male mice compared to control orchidectomized males, and was increased in muscle from male AR knockout mice that lacked DNA binding activity (AR(ΔZF2)) versus wildtype mice, demonstrating that myogenin is repressed by the androgen/AR pathway. The ubiquitin ligase Fbxo32 was repressed by 12 h dihydrotestosterone treatment in human skeletal muscle cell myoblasts, and c-Myc expression was decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle, and increased in AR(∆ZF2) muscle. The expression of a group of genes that regulate the transition from myoblast proliferation to differentiation, Tceal7 , p57(Kip2), Igf2 and calcineurin Aa, was increased in AR(∆ZF2) muscle, and the expression of all but p57(Kip2) was also decreased in testosterone-treated orchidectomized male muscle compared to control orchidectomized male muscle. We conclude that in males, androgens act via the AR in part to promote peak muscle mass by maintaining myoblasts in the proliferative state and delaying the transition to differentiation during muscle growth and development, and by suppressing ubiquitin ligase-mediated atrophy pathways to preserve muscle mass in adult muscle.
Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria, Australia.
Kesha
K
Rana
Nicole K L
NK
Lee
Jeffrey D
JD
Zajac
Helen E
HE
MacLean
D000818:Animals; D019703:Calcineurin / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000187:drug effects / Q000235:genetics; D013196:Dihydrotestosterone / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007335:Insulin-Like Growth Factor II / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000187:drug effects / Q000235:genetics*; D018482:Muscle, Skeletal; D032448:Myoblasts, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018008:Myogenin / Q000235:genetics*; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics; D009919:Orchiectomy; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics*; D044843:SKP Cullin F-Box Protein Ligases / Q000187:drug effects / Q000235:genetics*; D013739:Testosterone / Q000494:pharmacology
C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; C513121:IGF2 protein, mouse; D009124:Muscle Proteins; C489428:Myc protein, mouse; D018008:Myogenin; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D007335:Insulin-Like Growth Factor II; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; D019703:Calcineurin