Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

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 or 5a-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 b-catenin, were repressed, indicating modulation of the b-catenin pathway. DHT increased total levels of b-catenin protein, which accumulated in nuclei in vivo. Likewise, treatment of C2C12 myoblasts with both IGF1Ea and MGF C-terminal peptide increased nuclear b-catenin in vitro. Thus, we propose that androgenic anabolism involves early downregulation of Axin and induction of IGF1, leading to nuclear accumulation of b-catenin, a pro-myogenic, anti-adipogenic stem cell regulatory factor.

Chronic exposure to anabolic steroids induces the muscle expression of oxytocin and a more than fiftyfold increase in circulating oxytocin in cattle

“…The transition to a muscle phenotype favoring the slower subunits has been previously documented in steroid-treated cattle (10) and sheep (12) at the histological level. This is most likely attributable to the androgen component of the hormone implant, given its reported impact on murine quadriceps muscle gene expression (1), although the reverse trend, an increase in fast fibers, has been observed following androgen treatment in aged castrated rat soleus muscle (13). This may point to either species-, or musclespecific, diversity.…”

“…Evidence for indirect action comes from the observed induction of other known anabolic agents following steroid treatment. For example, treatment of soleus, a predominantly slow twitch muscle, from aged castrated rat, with 5␣-dihydrotestosterone induces IGF1 and the IGF1 splice variant mechano-growth factor within 24 h, leading to a molecular switch to a more type II muscle phenotype (13). Similarly, treatment of young castrated cattle with estradiol-17␤ increases the levels of growth hormone (GH) and IGF1 in plasma (5).…”

The Complexity of the IGF1 Gene Splicing, Posttranslational Modification and Bioactivity

“…Thus, during the last decade, many in vitro and in vivo studies have investigated the aspect of the differential IGF-I isoforms or their E-peptides actions in various conditions and pathologies (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). This concept was further supported by recent findings which revealed differential, E-peptide-or IGF-I isoform-specific signaling (31,33,34,(38)(39)(40).…”

Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

“…By contrast, Igf1 mRNA expression ( Figure 5C) and Igf2 mRNA expression (data not shown) increased at 16 weeks. While we do not fully understand the reason for elevated Igf1 mRNA in these mice, it is possible that compensatory pathways, such as androgens (37,38), or loss of feedback inhibition of IGF-1 via autocrine effects through its receptor (40), led to increased IGF-1 production. Histomorphometric analysis of the medial gastrocnemius from 6- and 16-week-old control and ΔIGF-1R mice (Figure 5 Unlike the ΔGHR mice, which gained weight postnatally, mice lacking IGF-1R in skeletal muscle failed to attain normal body weight as they aged ( Figure 5N).…”

“…Deletion of Ghr mRNA from skeletal muscle was confirmed by real-time PCR (Figure 2A), and importantly, removal of the GHR from skeletal muscle did not affect Igf1r mRNA expression levels ( Figure 2B). Expression of Igf1 mRNA in skeletal muscle was increased at 6 weeks ( Figure 2C), possibly a result of compensation by other pathways known to activate IGF-1 production in skeletal muscle, most likely androgens (37,38). However, Igf1 mRNA in ΔGHR mutants declined to levels below those observed in control animals by 16 weeks ( Figure 2C).…”