Stimulation of both estrogen and androgen receptors maintains skeletal muscle mass in gonadectomized male mice but mainly via different pathways.
Testosterone is a major regulator of muscle mass. Little is known whether this is due to a direct stimulation of the androgen receptor (AR) or mediated by aromatization of testosterone to estradiol (E(2)), the ligand for the estrogen receptors (ERs), in peripheral tissues. In this study, we differentiated between the effects mediated by AR and ER by treating orchidectomized (orx) male mice for 5 weeks with E(2) or the non-aromatizable androgen dihydrotestosterone (DHT). Both E(2) and DHT increased muscle weight and lean mass, although the effect was less marked after E(2) treatment. Studies of underlying mechanisms were performed using gene transcript profiling (microarray and real-time PCR) in skeletal muscle, and they demonstrated that E(2) regulated 51 genes and DHT regulated 187 genes, with 13 genes (=25% of E(2)-regulated genes) being regulated by both treatments. Both E(2) and DHT altered the expression of Fbxo32, a gene involved in skeletal muscle atrophy, affected the IGF1 system, and regulated genes involved in angiogenesis and the glutathione metabolic process. Only E(2) affected genes that regulate intermediary glucose and lipid metabolism, and only DHT increased the expression of genes involved in synaptic transmission and heme and polyamine biosynthesis. In summary, ER activation by E(2) treatment maintains skeletal muscle mass after orx. This effect is less marked than that of AR activation by DHT treatment, which completely prevented the effect of orx on muscle mass and was partly, but not fully, mediated via alternative pathways.
Svensson
Johan
J
Division of Endocrinology, Department of Internal Medicine, Institute of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
Movérare-Skrtic
Sofia
S
Windahl
Sara
S
Swanson
Charlotte
C
Sjögren
Klara
K
D000728:Androgens / Q000378:metabolism; D000818:Animals; D013196:Dihydrotestosterone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D018482:Muscle, Skeletal / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D009919:Orchiectomy; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000728:Androgens; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013196:Dihydrotestosterone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I