Resistance exercise for protection against glucocorticoids in aged skeletal muscle

项目总结/摘要 糖皮质激素性肌病是最常见的非炎症性肌病，影响约60%的患者， 糖皮质激素升高糖皮质激素肌病的诊断是肌肉萎缩和无力;然而， 肌病包括其它症状，例如胰岛素抵抗。老年人特别容易受到 肌病是由于老年肌肉对糖皮质激素更敏感，内源性糖皮质激素水平增加， 在老年人中超过50%，治疗关节炎和癌症等疾病的治疗性糖皮质激素 最常见于老年人。虽然已知糖皮质激素肌病在老年人中最普遍， 在这个高度脆弱的人群中缺乏预防肌病的治疗。我们最近 一份出版物表明，阻力运动可能是一种直接的方法，以保护老化的肌肉， 糖皮质激素肌病具体来说，我们表明，一轮阻力运动在年轻的肌肉减少 糖皮质激素受体的核转位是糖皮质激素 启动肌病。抗阻运动钝化细胞核转位的能力对 因为受体的激活在老年肌肉中诱导更严重的肌病。同样重要 对于老年人群，我们发现受体易位在运动后恢复期减少， 这表明，一次抗阻运动可能对抵抗运动有持久的保护作用。 糖皮质激素像阻力运动这样的肌肉靶向方法也可以让老年患者服用 处方糖皮质激素，以保持在非肌肉组织（例如， 癌性肿瘤）。在这项工作的延伸，我们的初步数据显示，一轮阻力运动可以 阻止糖皮质激素诱导的一些靶基因表达的变化，而另一些则出现 抵抗运动刺激。因为老年人很容易患上糖皮质激素性肌病， 由于糖皮质激素影响高达20%的基因组表达，因此了解糖皮质激素的作用是很重要的。 抗阻运动减弱老年肌肉中引发糖皮质激素肌病的信号的能力， 临床医生可以更有效地治疗这些老年患者。因此，本提案的目的是 确定抗阻运动的治疗潜力，以减轻启动糖皮质激素的过程 老年骨骼肌肌病具体目标1将定义糖皮质激素受体内的步骤 抗阻运动对年轻和老年肌肉造成破坏的激活过程。具体目标2 将根据年轻和老年肌肉中糖皮质激素靶基因的表达情况， 一次抗阻运动会影响运动调节基因的表达。这项试点研究将确定 抗阻运动可以减弱老年骨骼肌中引发糖皮质激素肌病的信号。 这些结果意义重大，因为它们将为临床医生提供有效使用的关键信息 抗阻运动作为预防老年人糖皮质激素性肌病综合策略的一部分。

Project Summary/Abstract Glucocorticoid myopathy is the most common noninflammatory myopathy affecting ~60% of those with elevated glucocorticoids. Glucocorticoid myopathy is diagnosed by muscle atrophy and weakness; however, the myopathy includes other symptoms such as insulin resistance. The elderly are particularly vulnerable to the myopathy as aged muscle is more sensitive to glucocorticoids, endogenous glucocorticoid levels are increased more than 50% in the elderly, and therapeutic glucocorticoids that treat conditions like arthritis and cancer are most prevalent in the elderly. While it is known that glucocorticoid myopathy is most prevalent in the elderly, there are a lack of treatments to prevent the myopathy in this highly vulnerable population. Our recent publication suggests resistance exercise could be an immediate way to protect aged muscle from glucocorticoid myopathy. Specifically, we show that a bout of resistance exercise in young muscle reduces nuclear translocation of the glucocorticoid receptor, a critical step in the process by which glucocorticoids initiate myopathy. The ability of resistance exercise to blunt nuclear translocation by is particularly important for the elderly because activation of the receptor induces a more severe myopathy in aged muscle. Also important for the elderly population, we show that receptor translocation is reduced in the post exercise recovery period, suggesting that a single bout of resistance exercise could have a lasting protective effect against glucocorticoids. A muscle targeted approach like resistance exercise will also allow elderly patients taking prescription glucocorticoids to keep getting therapeutic benefits of the hormone in non-muscle tissue (e.g. cancerous tumor). In extension of that work, our preliminary data show that a bout of resistance exercise can prevent the glucocorticoid-induced change in the expression of some target genes, while others appear resistant to the exercise stimulus. Because the elderly are so vulnerable to glucocorticoid myopathy, and because glucocorticoids influence expression of up to 20% of the genome, it is important to understand the capacity of resistance exercise to blunt the signals that initiate glucocorticoid myopathy in aged muscle so that clinicians can clinicians more effectively treat these elderly patients. Thus, the objective of this proposal is to define the therapeutic potential of resistance exercise to mitigate processes that initiate glucocorticoid myopathy in aged skeletal muscle. SPECIFIC AIM 1 will Define the steps within the glucocorticoid receptor activation process where resistance exercise imparts disruption in young and aged muscle. SPECIFIC AIM 2 will classify and characterize the glucocorticoid target genes in young and aged muscle based upon how a bout of resistance exercise affects hormone-regulated gene expression. This pilot study will define the extent to which resistance exercise can blunt the signals that initiate glucocorticoid myopathy in aged skeletal muscle. These outcomes are significant because they will provide key information for clinicians to effectively use resistance exercise as part of a comprehensive strategy to prevent glucocorticoid myopathy in the elderly.