Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of {beta}-catenin.
Androgens promote anabolism in the musculoskeletal system while generally repressing adiposity, leading to lean body composition. Circulating androgens decline with age, contributing to frailty, osteoporosis, and obesity; however, the mechanisms by which androgens modulate body composition are largely unknown. Here, we demonstrate that aged castrated rats develop increased fat mass, reduced muscle mass and strength, and lower bone mass. Treatment with testosterone or 5alpha-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable testosterone increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of IGF1 and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, monocyte nuclear factor, or myostatin. A genome-wide microarray screen was also performed to identify potential pro-myogenic genes that respond to androgen receptor activation in vivo within 24 h. Of 24 000 genes examined, 70 candidate genes were identified whose functions suggest initiation of remodeling and regeneration, including the type II muscle genes for myosin heavy chain type II and parvalbumin and the chemokine monocyte chemoattractant protein-1. Interestingly, Axin and Axin2, negative regulators of beta-catenin, were repressed, indicating modulation of the beta-catenin pathway. DHT increased total levels of beta-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear beta-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of beta-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.
Gentile
Michael A
MA
Department of Molecular Endocrinology, West Point, Pennsylvania 19486, USA.
Nantermet
Pascale V
PV
Vogel
Robert L
RL
Phillips
Robert
R
Holder
Daniel
D
Hodor
Paul
P
Cheng
Chun
C
Dai
Hongyue
H
Freedman
Leonard P
LP
Ray
William J
WJ
D000728:Androgens / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D060466:Axin Protein; D001823:Body Composition / Q000187:drug effects*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000378:metabolism*; D009919:Orchiectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000378:metabolism*
D000728:Androgens; D060466:Axin Protein; D012097:Repressor Proteins; D051176:beta Catenin; C519382:mechano-growth factor, rat; D007334:Insulin-Like Growth Factor I