Attenuation of denervation atrophy by nandrolone: molecular mechanisms

雄激素通过分子机制减轻肌肉萎缩 明白了。雄激素诺孕酮对肌肉萎缩影响的研究 通过切断神经瘫痪，我们发现萎缩的速度在7天内降低。 在神经切断后29天(35天)开始使用这种类固醇时开始使用诺龙 与肌肉泛素连接酶MAFbx和MuRF1表达减少有关。相反， 当在神经切断时开始使用诺龙时，它并没有减缓萎缩或减少 7天后(7天)MAFbx或MuRF1的表达。我们相信，这种模式提供了一种独特的 有机会了解南多隆延缓肌肉萎缩的分子机制， 并了解为什么肌肉在某些情况下对诺龙的有益影响具有抵抗性 条件。有趣的是，基因图谱显示，在35岁以下受南多龙影响的基因中， 不是7天，并且有可能调节肌肉大小的是FOXO1和RCAN2。RCAN2是 在骨骼肌中高水平表达，抑制钙调神经磷酸酶(一种蛋白质磷酸酶) 通过激活转录因子NFAT参与肌肉肥大。感兴趣，FOXO1 过度表达也会降低钙调神经磷酸酶的活性，可能是通过上调MAFbx[5-7]，提示 诺孕酮诱导的FOXO1和MAFbx水平的降低可能代表着第二个平行的 诺龙增加失神经肌肉钙调神经磷酸酶活性的机制。 失神经肌肉在早期对诺洛酮的不敏感很可能反映了 表达一种转录调节因子，它可以阻断诺龙的作用，或下调一种转录调节因子 对它来说是必要的。我们发现几种转录产物的表达水平有很大的差异 失神经骨骼肌中的协同调节因子在失神经后7天与35天时，最大 变化，减少了25倍，是Ankrd2。我们建议分析这些因素的影响 有关诺酮敏感性的转录辅助调节因子将为分子研究提供新的见解 肌肉决定因素对诺酮和其他雄激素的影响，并解释了这一有趣的现象 在某些病理生理条件下骨骼肌对雄激素的抵抗问题。 这项建议的主要目的是，在失神经萎缩的大鼠模型中，确定：1) 诺得龙增加失神经肌肉中钙调神经磷酸酶的活性，以及这种增加是否与此有关 钙调神经磷酸酶、RCAN_2和钙调神经磷酸酶上游调节因子水平的变化 钙调神经磷酸酶水平(FOXO1和MAFbx)；2)特定的转录辅助调节因子是否介导 抵抗诺孕酮减少萎缩和抑制MAFbx的作用。

Androgenic steroids reduce muscle atrophy through molecular mechanisms that are poorly understood. In studies of the effects of the androgenic steroid nandrolone on atrophy of muscle paralyzed by nerve transection, we have found that rates of atrophy are reduced within 7 days after beginning nandrolone when this steroid is started at 29 days after nerve transection (35 days) associated with reduced expression of the muscle ubiquitin ligases MAFbx and MuRF1. By contrast, when nandrolone was begun at the time of nerve transection, it did not slow atrophy or reduce expression of MAFbx or MuRF1 7 days later (7 days). We believe that this model provides a unique opportunity to understand the molecular mechanisms by which nandrolone slows muscle atrophy, and to understand why muscle is resistant to the beneficial effects of nandrolone under some conditions. Of interest, gene profiling revealed that, among genes affected by nandrolone at 35 but not 7 days, and potentially capable of regulating muscle size, were FOXO1 and RCAN2. RCAN2 is expressed at high levels in skeletal muscle, where it inhibits calcineurin, a protein phosphatase involved in muscle hypertrophy by activating the transcription factor NFAT. Of interest, FOXO1 overexpression also reduces calcineurin activity, possibly by upregulating MAFbx [5-7], suggesting that nandrolone-induced reductions in FOXO1 and MAFbx levels may represent a second, parallel mechanism by which nandrolone may increase calcineurin activity in denervated muscle. The insensitivity of denervated muscle to nandrolone at early time points most likely reflects expression of a transcriptional regulator that blocks nandrolone action, or downregulation of one that is necessary for it. We found large differences in expression levels of several transcriptional coregulators in denervated skeletal muscle at 7 versus 35 days after denervation, with the greatest change, a 25-fold decrease, being for Ankrd2. We propose that analysis of effects of these transcriptional coregulators on nandrolone sensitivity will provide new insights into molecular determinants of muscle to effects of nandrolone and other androgens and explain the intriguing problem of resistance of skeletal muscle to androgens under some pathophysiological conditions. Major Aims of this proposal are, in a rat model of denervation atrophy, to determine: 1) whether nandrolone increases calcineurin activity in denervated muscle, and whether such increases are due to nandrolone-dependent changes in levels of calcineurin, RCAN2, and upstream regulators of calcineurin levels (FOXO1 and MAFbx); 2) whether specific transcriptional coregulators mediate resistance to effects of nandrolone to reduce atrophy and repress MAFbx.