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Targeting Oxidative Stress to Prevent Vascular and Skeletal Muscle Dysfunction during Disuse

针对氧化应激预防废用期间的血管和骨骼肌功能障碍

基本信息

批准号：
10710166
负责人：
Joel Douglas Trinity
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10710166
关键词：
Acceleration Acute Address Aerobic Aging Animals Antioxidants Atrophic Bed Occupancy Bed rest Blood Vessels Data Data Reporting Disease Progression Elderly Epidemic Equilibrium Free Radical Scavenging Free Radicals Functional disorder Gene Expression Goals Health Hospitalization Human Hydrogen Peroxide Impairment Individual Injury Intervention Leg Link Measurement Measures Mitochondria Modeling Movement Muscle Proteins Muscle function Musculoskeletal System Nutrient Operative Surgical Procedures Outcome Outcome Measure Oxidation-Reduction Oxidative Stress Oxidative Stress Induction Oxygen Participant Pathway interactions Physiological Process Production Proteolysis Randomized Reactive Oxygen Species Recovery Role Serious Adverse Event Signal Pathway Skeletal Muscle System Testing Tissues Vascular Diseases Vascular System Veterans Vulnerable Populations age related aged antioxidant enzyme disability hospital readmission improved indexing insight mitochondrial dysfunction mitoquinone mortality muscle form muscle strength muscular system novel novel strategies nuclear factor-erythroid 2 older men older women preservation prevent primary outcome protein expression secondary outcome skeletal preservation

项目摘要

Disuse following injury, illness, or surgery is linked to functional deficiencies, hospital readmission, impaired recovery, and increased mortality. Older Veterans are particularly vulnerable to disuse as functional (vascular and skeletal muscle mitochondrial dysfunction) and structural (loss in muscle mass and strength) deficits are present as a consequence of the aging process. The accelerated declines that occur during disuse further deplete an already diminished physiological and functional reserve capacity. Current skeletal muscle-focused strategies to mitigate atrophy and losses in strength are ineffective and the mechanism(s) contributing to accelerated losses are unknown. Therefore, identifying the mechanism(s) and developing effective strategies to minimize losses in vascular and skeletal muscle function, systems that are inextricably linked to mobility, disease progression, and health, is critical to delay the onset of disability and preserve the health of older adults. Supported by preliminary and previous data, it is our central hypothesis that oxidative stress triggers the accelerated declines in vascular and skeletal muscle function during disuse. To mechanistically and comprehensively identify the obligatory role of oxidative stress in disuse-induced dysfunction two novel and fundamentally unique approaches to diminish oxidative stress are proposed including; 1) a mitochondrial targeted antioxidant (MitoQ; Aim 1) and 2) the nuclear factor erythroid-2-like 2 (Nrf2) activator, PB125 (Aim 2). A total of 72 healthy older men and women (> 65 yrs.) will be block randomized to 3 groups; CONTROL, MitoQ, and PB125. Five days of bed rest, a model of disuse mimicking acute hospitalization, will be used to evoke oxidative stress and losses in vascular and skeletal muscle function. In Specific Aim 1, participants will receive MitoQ (consisting of mitoquinone) during 5 days of bed rest. It is expected that MitoQ will blunt the increase in oxidative stress by limiting mitochondrial-derived reactive oxygen species (ROS) production leading to preserved vascular and skeletal muscle function, thereby revealing a critical role of mitochondrial-derived ROS. In Specific Aim 2, the novel Nrf2 activator, PB125, will be administered during 5 days of bed rest. It is expected that activation of Nrf2 with PB125 will restore the age-related dysfunction of the Nrf2 signaling pathway resulting in the induction of endogenous antioxidant enzymes that will, in turn, maintain redox balance induced by disuse. The primary outcome measure for both aims is the assessment of vascular function as measured by passive leg movement (PLM). Secondary outcome measures will assess the contributions of oxidative stress to the observed changes in vascular and skeletal muscle function before and after bed rest and will include direct measurements of free radicals, mitochondrial function and hydrogen peroxide production, markers of oxidative stress at the cellular, tissue, and systemic levels, changes in muscle mass and strength, and changes in muscle protein and gene expression that may be mechanistically linked to proteolysis and atrophy during disuse.

受伤、疾病或手术后的废用与功能缺陷、再入院、功能障碍有关恢复，死亡率增加。老年退伍军人特别容易因为功能（血管）而被废用和骨骼肌线粒体功能障碍）和结构（肌肉质量和力量损失）缺陷是由于老化过程而出现。废弃期间发生的加速下降进一步耗尽已经减弱的生理和功能储备能力。目前以骨骼肌为主减轻萎缩和力量损失的策略是无效的，并且导致的机制加速损失未知。因此，确定机制并制定有效的策略最大限度地减少血管和骨骼肌功能的损失，这些系统与活动、疾病密切相关进展和健康对于延缓残疾的发生和维护老年人的健康至关重要。在初步和先前数据的支持下，我们的中心假设是氧化应激触发废用期间血管和骨骼肌功能加速下降。机械地和全面确定氧化应激在废用引起的功能障碍中的必然作用，这两种新颖和提出了减少氧化应激的根本上独特的方法，包括： 1）线粒体靶向抗氧化剂（MitoQ；目标 1）和 2）核因子类红细胞 2 (Nrf2) 激活剂 PB125（目标 2）。总共 72 名健康老年男性和女性（> 65 岁）将被随机分为 3 组；控制，MitoQ，和PB125。五天卧床休息是一种模仿急性住院的废用模型，将用于唤起氧化应激以及血管和骨骼肌功能的丧失。在具体目标 1 中，参与者将获得 MitoQ（由米托醌组成）卧床休息 5 天。预计 MitoQ 将抑制通过限制线粒体衍生的活性氧 (ROS) 产生来减少氧化应激，从而保留血管和骨骼肌功能，从而揭示线粒体衍生的 ROS 的关键作用。具体来说目标 2，新型 Nrf2 激活剂 PB125，将在卧床休息 5 天期间施用。预计激活 Nrf2 与 PB125 的结合将恢复 Nrf2 信号通路与年龄相关的功能障碍，从而导致诱导内源性抗氧化酶的数量反过来又会维持因废弃而引起的氧化还原平衡。初级这两个目标的结果测量是通过被动腿部运动来评估血管功能（产品生命周期管理）。次要结果指标将评估氧化应激对观察到的变化的贡献卧床休息前后的血管和骨骼肌功能，包括直接测量自由自由基、线粒体功能和过氧化氢的产生、细胞氧化应激的标志物、组织和全身水平、肌肉质量和力量的变化以及肌肉蛋白质和基因的变化表达可能在机械上与废弃期间的蛋白水解和萎缩有关。