Resistance exercise to mitigate glucocorticoid myopathy during Alzheimer’s

抗阻运动可减轻阿尔茨海默病期间的糖皮质激素肌病

基本信息

批准号：
10667849
负责人：
Bradley S Gordon
金额：
$ 7.43万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-15 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667849
关键词：
3xTg-AD mouse Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Categories Cell physiology Classification Complex Contralateral DNA receptor Data Dexamethasone Electric Stimulation Exercise Frequencies Gene Expression Genes Glucocorticoid Receptor Glucocorticoids Health Hormones Human Impaired cognition Knowledge Laboratories Life Measures Mediating Metabolic Mission Modeling Mus Muscle Muscle function Myopathy Nuclear Nuclear Translocation Organism Outcome Pathology Pathway Analysis Phosphorylation Pilot Projects Population Process Production Proteins Public Health Publications RNA Randomized Receptor Activation Recovery Research Response Elements Senile Plaques Signal Transduction Skeletal Muscle Testing Time United States National Institutes of Health Wild Type Mouse abeta accumulation cognitive function disability falls novel preservation prevent promoter resistance exercise response sciatic nerve tibialis anterior muscle transcriptome transcriptome sequencing

3xTg-AD mouse Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Categories Cell physiology Classification Complex Contralateral DNA receptor Data Dexamethasone Electric Stimulation Exercise Frequencies Gene Expression Genes Glucocorticoid Receptor Glucocorticoids Health Hormones Human Impaired cognition Knowledge Laboratories Life Measures Mediating Metabolic Mission Modeling Mus Muscle Muscle function Myopathy Nuclear Nuclear Translocation Organism Outcome Pathology Pathway Analysis Phosphorylation Pilot Projects Population Process Production Proteins Public Health Publications RNA Randomized Receptor Activation Recovery Research Response Elements Senile Plaques Signal Transduction Skeletal Muscle Testing Time United States National Institutes of Health Wild Type Mouse abeta accumulation cognitive function disability falls novel preservation prevent promoter resistance exercise response sciatic nerve tibialis anterior muscle transcriptome transcriptome sequencing

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项目摘要

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.

项目摘要/摘要健康的骨骼肌减慢了阿尔茨海默氏症患者的认知能力下降。糖皮质激素增加了3倍阿尔茨海默氏症患者发生的产生使其骨骼肌容易受到糖皮质激素的影响。诱导的肌病是最常见的，有毒的，非炎性肌肉疾病的肌病糖皮质激素。虽然这种肌病会降低肌肉健康和增强认知能力下降，但仍有没有办法预防该人群中的糖皮质激素肌病。无法治疗糖皮质激素肌病阿尔茨海默氏症患者限制了临床保留认知功能的能力。尽管这个问题，我们的新数据表明抵抗运动可能是阿尔茨海默氏病患者钝化的一种直接方法启动糖皮质激素肌病。特别是，我们的实验室最近在健康肌肉中发表的出版物表明抗性运动的回合减少了糖皮质激素受体的核易位，这是糖皮质激素引发肌病的过程。糖皮质激素受体会引发肌病通过更改肌肉转录组的一部分。根据，我们的新初步数据表明耐药性运动还将逆转一些糖皮质激素靶基因的糖皮质激素介导的诱导。尽管有望作为一种疗法，但阿尔茨海默氏病诱导了一种新颖的肌肉病理学损害骨骼肌功能的淀粉样蛋白β斑块的积累耐药性运动在减轻引发糖皮质激素肌病的信号方面较少或无效。所以，该提案的目的是测试阿尔茨海默氏症的骨骼肌疾病病理学是否影响 AIM 1将定义阿尔茨海默氏症肌肉疾病病理学对减少糖皮质激素抗性运动能力的影响骨骼肌的受体激活。 AIM 2将对糖皮质激素靶基因进行分类和表征根据他们的马酮调节的方式基因表达对抗性运动的反应。总之，这项试验研究将定义在多大程度上抵抗运动可以钝化在阿尔茨海默氏症存在下引发糖皮质激素肌病的信号肌肉病理学。这些结果很重要，因为它们将为临床医生提供关键信息有效地使用抗性运动作为防止糖皮质激素肌病和的综合策略的一部分在阿尔茨海默氏症人口中保留认知功能。