Resistance exercise to mitigate glucocorticoid myopathy during Alzheimer’s

项目总结/摘要 健康的骨骼肌可以减缓阿尔茨海默病患者的认知能力下降。糖皮质激素的三倍增加 阿尔茨海默氏症患者体内产生的糖皮质激素使他们的骨骼肌容易受到糖皮质激素的影响， 诱发性肌病，这是最常见的，毒性，非炎症性肌肉疾病，在那些升高 糖皮质激素虽然这种肌病会降低肌肉健康和增加认知能力下降， 没有办法预防糖皮质激素性肌病。无法治疗糖皮质激素肌病， 老年痴呆症患者限制了临床医生保持认知功能的能力。尽管有这个问题，我们的新数据 表明抗阻运动可能是阿尔茨海默氏症患者减弱信号的直接方法， 引发糖皮质激素肌病。具体来说，我们实验室最近在健康肌肉中的出版物表明， 一次抗阻运动减少了糖皮质激素受体的核转位，而糖皮质激素受体的核转位是免疫系统中的一个关键步骤。 糖皮质激素引发肌病的过程。糖皮质激素受体在大范围内引发肌病 部分是通过改变肌肉转录组。因此，我们新的初步数据显示， 抗阻运动还将逆转糖皮质激素介导的某些糖皮质激素靶基因的诱导。 虽然作为一种治疗方法很有前途，但阿尔茨海默病诱导了一种新的肌肉病理学，其特征在于： β淀粉样蛋白斑块的积累，损害骨骼肌功能，这可能使 抗阻运动在减轻引发糖皮质激素肌病的信号方面较少或无效。因此，我们认为， 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学是否会影响 抗阻运动的能力，以减轻信号，启动糖皮质激素肌病。目标1将定义 阿尔茨海默病肌肉病变对抗阻运动降低糖皮质激素水平的影响 骨骼肌中的受体激活。目的2对糖皮质激素靶基因进行分类和鉴定 在健康肌肉和患有阿尔茨海默病的肌肉中， 基因表达对一次抗阻运动有反应。总之，这项试点研究将确定在多大程度上 抗阻运动可以减弱阿尔茨海默病患者出现糖皮质激素肌病的信号 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， 有效地使用抗阻运动作为预防糖皮质激素肌病的综合策略的一部分， 保持老年痴呆症患者的认知功能。

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.