Center of Excellence for the Medical Consequences of Spinal Cord Injury, James J. Peters VA Medical Center, 953 Southern Boulevard, Bronx, New York 10468, USA.
Endocrinology. 2010 Mar;151(3):1050-9. doi: 10.1210/en.2009-0530. Epub 2009 Dec 23.
Glucocorticoids are a well-recognized and common cause of muscle atrophy that can be prevented by testosterone. However, the molecular mechanisms underlying such protection have not been described. Thus, the global effects of testosterone on dexamethasone-induced changes in gene expression were evaluated in rat gastrocnemius muscle using DNA microarrays. Gene expression was analyzed after 7-d administration of dexamethasone, dexamethasone plus testosterone, or vehicle. Dexamethasone changed expression of 876 probe sets by at least 2-fold. Among these, 474 probe sets were changed by at least 2-fold in the opposite direction in the dexamethasone plus testosterone group (genes in opposition). Major biological themes represented by genes in opposition included IGF-I signaling, myogenesis and muscle development, and cell cycle progression. Testosterone completely prevented the 22-fold increase in expression of the mammalian target of rapamycin (mTOR) inhibitor regulated in development and DNA damage responses 1 (REDD1), and attenuated dexamethasone induced increased expression of eIF4E binding protein 1, Forkhead box O1, and the p85 regulatory subunit of the IGF-I receptor but prevented decreased expression of IRS-1. Testosterone attenuated increases in REDD1 protein in skeletal muscle and L6 myoblasts and prevented dephosphorylation of p70S6 kinase at the mTOR-dependent site Thr389 in L6 myoblast cells. Effects of testosterone on REDD1 mRNA levels occurred within 1 h, required the androgen receptor, were blocked by bicalutamide, and were due to inhibition of transcriptional activation of REDD1 by dexamethasone. These data suggest that testosterone blocks dexamethasone-induced changes in expression of REDD1 and other genes that collectively would otherwise down-regulate mTOR activity and hence also down-regulate protein synthesis.
糖皮质激素是导致肌肉萎缩的公认常见原因，而睾酮可预防肌肉萎缩。然而，其保护机制尚未被描述。因此，本研究采用 DNA 微阵列评估了睾酮对大鼠腓肠肌中地塞米松诱导的基因表达变化的整体影响。在给予地塞米松、地塞米松加睾酮或载体 7d 后分析基因表达。地塞米松使 876 个探针集的表达至少增加 2 倍。其中，地塞米松加睾酮组中有 474 个探针集的表达至少增加 2 倍（相反方向的基因）。相反方向的基因所代表的主要生物学主题包括 IGF-1 信号、成肌和肌肉发育以及细胞周期进展。睾酮完全阻止了哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂发育和 DNA 损伤反应 1（REDD1）的 22 倍表达增加，并减弱了地塞米松诱导的 eIF4E 结合蛋白 1、叉头框 O1 和 IGF-1 受体 p85 调节亚基的表达增加，但防止 IRS-1 表达降低。睾酮减弱了骨骼肌和 L6 成肌细胞中 REDD1 蛋白的增加，并防止了 L6 成肌细胞中 mTOR 依赖性 Thr389 位点 p70S6 激酶的去磷酸化。睾酮对 REDD1 mRNA 水平的影响发生在 1h 内，需要雄激素受体，被比卡鲁胺阻断，并且是由于地塞米松抑制了 REDD1 的转录激活。这些数据表明，睾酮阻断了地塞米松诱导的 REDD1 和其他基因表达的变化，这些基因共同下调 mTOR 活性，从而也下调蛋白质合成。
