Glucocorticoid control of gene expression during skeletal muscle atrophy

骨骼肌萎缩或萎缩是人类的主要健康问题。 问题。制动、神经损伤、恶病质、败血症和衰老都会导致显著的和可能的 甚至危及生命的骨骼肌块的减少到损害足够的非卧床或 呼吸功能。肾上腺糖皮质激素也是骨骼肌的有效诱导剂 萎缩。糖皮质激素的生理水平支持脓毒症、肾功能衰竭和 其他分解代谢情况。此外，合成的糖皮质激素通常被认为是有效的。 消炎药但长期使用会导致衰弱的高血糖、胰岛素抵抗和 骨骼、软骨和肌肉的丧失。新的“选择性”糖皮质激素受体配体已被描述 抑制炎症性基因表达，但对上调其他类别的 糖皮质激素应答基因，从而显示出良好的药物潜力。然而，没有一个人做到了 对骨骼肌的影响进行了评估。此外，目前还没有药物可直接用于 在任何情况下减轻或防止肌肉萎缩，包括糖皮质激素治疗。 选择性地抑制骨骼肌中糖皮质激素受体的作用将提供一个机会 缓解各种情况下的萎缩。事实上，激活IGF-1或β2肾上腺素能 受体强烈抑制糖皮质激素诱导的萎缩。这种抑制的分子细节是 人们对此知之甚少，因为它们各自使用的信号转导通路是不同的还是重叠的 受体阻断糖皮质激素受体活性。因此，我们建议1)确定相对 MuRFt和MAFbx基因在糖皮质激素所致骨骼肌萎缩中的作用 最近开发的选择性抗炎性糖皮质激素受体配体对肌肉的作用 萎缩与MuRF1和MAFbx基因转录，以及3)研究 糖皮质激素诱导的MuRF1基因的调节，尤其是糖皮质激素的相反作用 IGF-1和β2肾上腺素能激动剂。新开发的遗传资源、药理工具和 分子技术可以用来实现这些目标。因此，这项提议代表了一种 应用糖皮质激素受体新概念和尖端技术的机会 直接作用于高度医学上相关的骨骼肌萎缩问题。

Skeletal muscle wasting, or atrophy, is a major human health issue. Immobilization, nerve damage, cachexia, sepsis, and aging all induce significant and possibly even life-threatening losses in skeletal muscle mass to the point of impairing adequate ambulatory or respiratory function. Adrenal glucocorticoid hormones are also potent inducers of skeletal muscle atrophy. Physiological levels of glucocorticoids support muscle atrophy in sepsis, renal failure, and other catabolic conditions. In addition, synthetic glucocorticoids are commonly prescribed as potent anti-inflammatory drugs but prolonged use leads to debilitating hyperglycemia, insulin resistance, and bone, cartilage, and muscle loss. New "selective" glucocorticoid receptor ligands have been described that repress inflammatory gene expression but are less potent at up- regulation of other classes of glucocorticoid responsive genes, thus showing good pharmaceutical potential. However, none have been evaluated for effects on skeletal muscle. Furthermore, no drugs are currently available to directly alleviate or prevent muscle atrophy under any circumstances, including glucocorticoid treatment. Inhibition of glucocorticoid receptor action selectively in skeletal muscle would present an opportunity to alleviate atrophy under a variety of conditions. Indeed, activation of either the IGF-1 or beta2 adrenergic receptors strongly inhibits glucocorticoid induced atrophy. The molecular details of this inhibition are poorly understood, as is whether distinct or overlapping signal transduction pathways are used by each receptor to block glucocortcoid receptor activity. Therefore, we propose to 1) Determine the relative contribution of MuRFt and MAFbx genes to glucocorticoid induced skeletal muscle atrophy, 2) Evaluate recently developed selective anti-inflammatory glucocorticoid receptor ligands for effects on muscle atrophy and MuRF1 and MAFbx gene transcription, and 3) Investigate molecular details of glucocorticoid-induced regulation of the MuRF1 gene, with particular focus on the opposing actions of IGF-1 and beta2 adrenergic agonists. Newly developed genetic resources, pharmacological tools, and molecular techniques are available to accomplish these aims. Thus, this proposal represents an opportunity to apply new concepts and cutting-edge technology regarding glucocorticoid receptor function directly to the highly medically relevant problem of skeletal muscle atrophy.