Mechanism through which chronically elevated mTOR activity impairs aged muscle recovery after disuse atrophy

长期升高的 mTOR 活性损害废用性萎缩后老年肌肉恢复的机制

基本信息

批准号：
10473096
负责人：
Benjamin Francis Miller
金额：
--
依托单位：
OKLAHOMA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10473096
关键词：
Acceleration Acute Address Adult Animals Atrophic Bed rest Biochemical Biology CCI-779 Chronic Chronic Disease Contractile Proteins Data Deterioration Disuse Atrophy Elderly Essential Amino Acids FRAP1 gene Failure Fibrosis Fractionation Functional disorder General Population Genetic Translation Goals Hindlimb Suspension Histology Hospitalization Human Image Impairment Inbred BN Rats Individual Inpatients Isotope Labeling Kinetics Knowledge Length of Stay Maintenance Mitochondria Mitochondrial Proteins Modeling Morphology Muscle Muscle function Muscular Atrophy Outcome Procedures Proteins Proteomics Rattus Recording of previous events Recovery Resistance Resolution Signal Transduction Sirolimus Skeletal Muscle Stress Tail Testing Tissues Tracer Translating Veterans Work age related aged base comorbidity critical period disability experimental study frailty functional outcomes improved innovation juvenile animal mTOR Inhibitor mTOR inhibition mechanotransduction military veteran mitochondrial dysfunction muscle aging muscle form muscle strength normal aging novel novel strategies preservation prevent protein degradation sarcopenia secondary outcome skeletal muscle wasting transcriptome sequencing

项目摘要

SUMMARY Older Veterans have a higher burden of comorbid chronic diseases compared to the general population, resulting in more frequent inpatient hospitalizations. A consequence of frequent and recurring hospitalizations is the acceleration of age-related loss of skeletal muscle mass and strength (sarcopenia). The combined effect of sarcopenia and hospitalization exacerbates muscle dysfunction since older adults do not adequately recover from bedrest placing them on an accelerated trajectory toward loss of independence. Therefore, the period around hospitalization is a critical period to intervene to prevent disability, loss of independence, and frailty in Veterans. It is not clear why skeletal muscle in older individuals is resistant to regrowth after a period of atrophy. Further, current strategies to enhance regrowth in older skeletal muscle remain largely ineffective. The proposed work is significant because it provides evidence that mTOR activation is the cause, not the solution, to the failure to recover muscle after disuse. The current proposal is innovative in that it goes against current therapies that were based on data from young animals; it proposes three independent but overlapping mechanisms; and it uses sophisticated combined isotope labeling and proteomic approaches to study the periods around disuse atrophy. The overall hypothesis of this proposal is that that chronically activated mTOR in aged skeletal muscle impairs the recovery of muscle mass/function after a period of disuse. To test this overall hypothesis, we will use old (28 mo) F344/BN rats with and without an mTOR inhibitor (rapamycin (Rapa)) to address three specific aims that determine if inhibiting chronic mTOR activity in older muscle: 1) corrects the mitochondrial dysfunction that impairs muscle recovery after a period of HU, 2) improves the proteostatic stress that impairs muscle recovery after a period of HU, and 3) helps resolve fibrosis that impairs muscle recovery after a period of HU. Our hypotheses are that suppression of chronically active mTOR activity will: 1) increase the selective translation of mRNA to improve mitochondrial protein remodeling, improve the deterioration of network connectivity, and improve mitochondrial function, 2) improve proteostatic maintenance during RE, and 3) reduce muscle fibrosis to improve mechanotransduction during RE. For these specific aims we will use our innovative targeted and discovery-based kinetic proteomics along with novel (e.g. mitochondrial imaging) and well-established secondary outcomes, including functional outcomes, to support our proteomic outcomes. It is hoped that these experiments will clarify the underlying cause of failed recovery in muscle of older Veterans, and whether we should fundamentally change the approach to enhance recovery after disuse in aged muscle. This knowledge could help prevent the accelerated progression to a disability threshold for a significant number of older Veterans.

概括与一般人群相比，老年退伍军人患有慢性共病的负担更高，因此更频繁的住院治疗。频繁且反复住院的后果是加速与年龄相关的骨骼肌质量和力量损失（肌肉减少症）。综合作用由于老年人无法充分康复，肌肉减少症和住院会加剧肌肉功能障碍卧床休息使他们加速失去独立性。因此，该时期住院期间是进行干预以防止残疾、丧失独立性和身体虚弱的关键时期退伍军人。目前尚不清楚为什么老年人的骨骼肌在萎缩一段时间后难以再生。此外，目前促进老年骨骼肌再生的策略在很大程度上仍然无效。拟议的这项工作意义重大，因为它提供了证据表明 mTOR 激活是失败的原因，而不是解决方案停用后恢复肌肉。当前的提议是创新的，因为它反对当前的疗法基于幼年动物的数据；它提出了三个独立但重叠的机制；和它使用复杂的组合同位素标记和蛋白质组学方法来研究废弃时期萎缩。该提议的总体假设是，老年骨骼肌中的 mTOR 长期激活在停用一段时间后会损害肌肉质量/功能的恢复。为了检验这个总体假设，我们将使用使用或不使用 mTOR 抑制剂（雷帕霉素 (Rapa)）的老年（28 个月）F344/BN 大鼠，以实现三个特定目标确定是否抑制老年肌肉中的慢性 mTOR 活性：1) 纠正线粒体功能障碍 HU 一段时间后会损害肌肉恢复，2) 改善损害肌肉恢复的蛋白质静压力 HU 期后，3) 帮助解决 HU 期后损害肌肉恢复的纤维化。我们的假设抑制长期活跃的 mTOR 活性将：1）增加 mRNA改善线粒体蛋白质重塑，改善网络连接恶化，以及改善线粒体功能，2) 改善 RE 期间的蛋白质维持，3) 减少肌肉纤维化改善 RE 期间的力传导。为了实现这些具体目标，我们将利用我们的创新目标和基于发现的动力学蛋白质组学以及新颖的（例如线粒体成像）和成熟的次要结果，包括功能结果，以支持我们的蛋白质组结果。希望这些实验将阐明老年退伍军人肌肉恢复失败的根本原因，以及我们是否可以应从根本上改变促进老化肌肉废弃后恢复的方法。这些知识可以帮助防止大量老年退伍军人加速发展到残疾阈值。