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
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
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DOI：
10.1677/jme-09-0048
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发表时间：
2010-01-01
影响因子：
3.5
通讯作者：
Ray, William J.
中科院分区：
文献类型：
--
作者：
Gentile, Michael A.;Nantermet, Pascale V.;Ray, William J.
雄激素促进肌肉骨骼系统的合成代谢，同时通常抑制肥胖，从而导致瘦身体成分。循环雄激素随着年龄的增长而下降，导致虚弱、骨质疏松和肥胖；然而，雄激素调节身体成分的机制在很大程度上尚不清楚。在这里，我们证明老年去势大鼠的脂肪量增加，肌肉质量和力量减少，骨量降低。用睾酮或 5α-二氢睾酮 (DHT) 治疗可以逆转对肌肉和脂肪组织的影响，而只有芳香化睾酮才能增加骨量。在第一周，DHT 短暂地增加比目鱼肌核密度并诱导 IGF1 及其剪接变体机械生长因子 (MGF) 的表达，而没有对生肌因子 MyoD、肌细胞生成素、单核细胞核因子或肌生长抑制素的早期调节。还进行了全基因组微阵列筛选，以确定在 24 小时内对体内雄激素受体激活做出反应的潜在促肌原基因。在检查的 24 000 个基因中，鉴定出 70 个候选基因，其功能表明重塑和再生的启动，包括 II 型肌球蛋白重链和小清蛋白的 II 型肌肉基因以及趋化因子单核细胞趋化蛋白-1。有趣的是，β-连环蛋白的负调节因子 Axin 和 Axin2 受到抑制，表明 β-连环蛋白途径受到调节。 DHT 增加了 β-连环蛋白的总水平，并在体内积累在细胞核中。同样，体外用 IGF1Ea 和 MGF C 末端肽处理 C2C12 成肌细胞会增加核 β-连环蛋白。因此，我们认为雄激素合成代谢涉及 Axin 的早期下调和 IGF1 的诱导，导致 β-catenin 的核积累，β-catenin 是一种促肌生成、抗脂肪生成的干细胞调节因子。
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 5 alpha-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.