Resistance exercise for protection against glucocorticoids in aged skeletal muscle

项目摘要/摘要 糖皮质激素性肌病是最常见的非炎症性肌病，影响到约60%的 糖皮质激素升高。糖皮质激素性肌病的诊断是肌肉萎缩和无力；然而， 肌病还包括其他症状，如胰岛素抵抗。老年人特别容易受到 肌病随着年龄的增长肌肉对糖皮质激素更敏感，内源性糖皮质激素水平升高 超过50%的老年人，以及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性肌病在老年人中最常见， 在这个高度脆弱的人群中，缺乏预防肌病的治疗方法。我们最近 研究表明，阻力训练可能是一种直接保护老化肌肉的方法 糖皮质激素性肌病。具体地说，我们表明，年轻肌肉中的一轮阻力运动可以减少 糖皮质激素受体的核转位，这是糖皮质激素 启动肌病治疗。抵抗力锻炼钝化核移位的能力对 老年人是因为该受体的激活会导致老年肌肉出现更严重的肌病。同样重要的是 对于老年人群，我们发现在运动后恢复期受体易位减少， 这表明，单轮抗阻训练可能会对 糖皮质激素。像阻力练习这样的肌肉靶向方法也将允许老年患者服用 处方糖皮质激素，以保持激素在非肌肉组织中的治疗效果(例如 癌症)。作为这项工作延伸，我们的初步数据显示，一轮抵抗力练习可以 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%的基因组的表达，因此了解 抵抗力训练能够减弱引发老年肌肉糖皮质激素性肌病的信号，从而 临床医生可以更有效地治疗这些老年患者。因此，这项提案的目标是 确定阻力运动的治疗潜力，以缓解启动糖皮质激素的过程 老年骨骼肌的肌病。特定的AIM 1将定义糖皮质激素受体内的步骤 抵抗力训练对年轻和老年肌肉造成破坏的激活过程。特定目标2 将对年轻和老年肌肉中的糖皮质激素靶基因进行分类和表征 一轮抗阻运动会影响荷尔蒙调节的基因表达。这项初步研究将确定 抵抗力训练可以减弱引发老年骨骼肌糖皮质激素性肌病的信号。 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 抵抗力训练是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.