Resistance exercise to mitigate glucocorticoid myopathy during Alzheimer’s

项目摘要/摘要 健康的骨骼肌可以减缓阿尔茨海默病患者的认知衰退。糖皮质激素的3倍增长 阿尔茨海默氏症患者体内产生的物质使他们的骨骼肌容易受到糖皮质激素的影响。 诱发性肌病，这是肥胖者最常见的毒性、非炎症性肌肉疾病 糖皮质激素。虽然这种肌病会降低肌肉健康并加剧认知能力下降，但有 在这一人群中没有预防糖皮质激素性肌病的方法。无法治疗糖皮质激素性肌病 阿尔茨海默氏症患者限制了临床医生保持认知功能的能力。尽管存在这个问题，我们的新数据 表明抵抗运动可能是阿尔茨海默氏症患者减弱信号的直接方法 引发糖皮质激素性肌病。具体地说，我们实验室最近在《健康肌肉》上发表的文章显示， 一轮抗阻运动减少了糖皮质激素受体的核转位，这是 糖皮质激素引发肌病的过程。糖皮质激素受体在大肌病发病中的作用 部分通过改变肌肉转录组。因此，我们新的初步数据显示，一轮 抵抗运动还将逆转糖皮质激素介导的一些糖皮质激素靶基因的诱导。 尽管阿尔茨海默病有望成为一种治疗方法，但它会引发一种新的肌肉病理，其特征是 损害骨骼肌功能的淀粉样β-斑块积聚，可能会导致 抵抗力运动在缓解引发糖皮质激素性肌病的信号方面较少或无效。因此， 这项建议的目的是测试阿尔茨海默氏症骨骼肌疾病的病理是否影响 抗阻运动缓解引发糖皮质激素性肌病的信号的能力。目标1将定义 阿尔茨海默病肌肉病病理对抵抗性运动减少糖皮质激素能力的影响 骨骼肌中的受体激活。目标2将对糖皮质激素靶基因进行分类和表征 在健康的肌肉和阿尔茨海默病的肌肉中，他们的激素是如何调节的 基因表达对一轮抵抗力训练做出反应。总而言之，这项初步研究将确定 抵抗力运动可以钝化阿尔茨海默病患者引发糖皮质激素性肌病的信号 肌肉病理学。这些结果意义重大，因为它们将为临床医生提供关键信息 有效利用抵抗力训练作为预防糖皮质激素性肌病的综合策略的一部分 保护阿尔茨海默氏症患者的认知功能。

Project Summary/Abstract Healthy skeletal muscle slows cognitive decline in Alzheimer’s patients. The 3-fold increase in glucocorticoid production that occurs in Alzheimer’s patients renders their skeletal muscle vulnerable to glucocorticoid- induced myopathy, which is the most common, toxic, non-inflammatory muscle disease in those with elevated glucocorticoids. While this myopathy would decrease muscle health and augment cognitive decline, there are no ways to prevent glucocorticoid myopathy in this population. The inability to treat glucocorticoid myopathy in Alzheimer’s patients limits a clinician’s ability to preserve cognitive function. Despite this issue, our new data show that resistance exercise may be an immediate way for Alzheimer’s patients to blunt the signals that initiate glucocorticoid myopathy. Specifically, our laboratory’s recent publication in healthy muscle shows that a bout of resistance exercise reduces nuclear translocation of the glucocorticoid receptor, a critical step in the process by which glucocorticoids initiate myopathy. The glucocorticoid receptor initiates the myopathy in large part by changing the muscle transcriptome. Accordingly, our new preliminary data show that a bout of resistance exercise will also reverse the glucocorticoid-mediated induction of some glucocorticoid target genes. While promising as a therapy, Alzheimer’s disease induces a novel muscle pathology characterized by accumulation of amyloid-beta plaques that compromises skeletal muscle function, which could render resistance exercise less- or ineffective at mitigating the signals that initiate glucocorticoid myopathy. Therefore, the objective of this proposal is to test whether Alzheimer’s skeletal muscle disease pathology affects the ability of resistance exercise to mitigate the signals that initiate glucocorticoid myopathy. Aim 1 will define the impact of Alzheimer’s muscle disease pathology on the ability of resistance exercise to reduce glucocorticoid receptor activation in the skeletal muscle. Aim 2 will classify and characterize the glucocorticoid target genes in healthy muscle and muscle with Alzheimer’s disease pathology based upon how their hormone-regulated gene expression responds to a bout of resistance exercise. In all, this pilot study will define the extent to which resistance exercise can blunt the signals that initiate glucocorticoid myopathy in the presence of Alzheimer’s muscle pathology. 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 and preserve cognitive function in the Alzheimer’s population.