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This Article Accepted manuscript (PDF) All Versions of this Article: JME-09-0048v1 JME-09-0048v2 JME-09-0048v3    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gentile, M. A Articles by Ray, W. J PubMed PubMed Citation Articles by Gentile, M. A Articles by Ray, W. J

M Gentile, Molecular Endocrinology and Bone Biology, Merck & Co, West Point, United States
P Nantermet, Molecular Endocrinology and Bone Biology, Merck & Co, West Point, United States
R Vogel, Molecular Endocrinology and Bone Biology, Merck & Co, West Point, United States
R Phillips, Molecular Profiling, Merck & Co, West Point, United States
D Holder, Biometrics, Merck & Co, West Point, United States
P Hodor, Molecular Profiling, Merck & Co, West Point, United States
H Dai, Molecular Profiling, Merck & Co, West Point, United States
C Cheng, Molecular Profiling, Merck & Co, Seattle, United States
L Freedman, Molecular Endocrinology, Merck & Co, West Point, United States
W Ray, Alzheimer's Research, Merck Research Labs, West Point, United States

Michael A Gentile, Email: michael_gentile{at}merck.com

Abstract

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 (T) or 5alpha-dihydrotestosterone (DHT) reverses the effects on muscle and adipose tissues while only aromatizable T increased bone mass. During the first week, DHT transiently increased soleus muscle nuclear density and induced expression of insulin-like growth factor-1 (IGF-1) and its splice variant mechano growth factor (MGF) without early regulation of the myogenic factors MyoD, myogenin, MNF, 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 hours. 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 II and parvalbumin and the chemokine MCP-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 IGF-1Ea and MGF c-terminal peptide increased nuclear beta-catenin in vitro. Thus we propose that androgenic anabolism involves downregulation of Axin, and induction of IGF-1, leading to nuclear accumulation of beta-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.