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

• 批准号: 10292887
• 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
• 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/10292887
• 关键词: 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; Oxygen; Participant; Pathway interactions; Physiological; Plant Roots; Process; Production; Proteolysis; Randomized; Reactive Oxygen Species; Recovery; Role; Serious Adverse Event; Signal Pathway; Skeletal Muscle; Structure; 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

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、疾病或手术后停用与功能缺陷、再次住院、受损有关 恢复，并增加死亡率。老年退伍军人特别容易因功能性(血管)而停用 和骨骼肌线粒体功能障碍)和结构性(肌肉质量和力量丧失)缺陷 作为老化过程的结果而出现的。在停用期间出现的加速下降进一步 耗尽已经减少的生理和功能储备能力。当前关注的骨骼肌 缓解萎缩和力量丧失的策略无效，机制(S)促成 加速损失是未知的。因此，找出机制(S)并制定有效的战略来 最大限度地减少血管和骨骼肌功能的损失，这些系统与行动不便、疾病 进展和健康对于延缓残疾的发生和保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了 在停用期间血管和骨骼肌功能加速下降。机械地，机械地 全面确认氧化应激在废用所致功能障碍中的强制性作用 我们提出了从根本上减轻氧化应激的独特方法，包括：1)线粒体 靶向抗氧化剂(MitoQ；目标1)和2)核因子红系2(Nrf2)激活剂PB125(目标2)。 共有72名健康的老年男性和女性(65岁)。将随机分成3组：对照组、MitoQ组、 和PB125。五天的卧床休息，一种模仿急性住院的废用模式，将被用来唤起 氧化应激与血管和骨骼肌功能的丧失。在具体目标1中，参与者将获得 卧床5天期间服用MitoQ(由丝裂原苯二酚组成)。预计MitoQ将抑制 通过限制线粒体衍生的活性氧(ROS)的产生而导致的氧化应激 血管和骨骼肌功能，从而揭示了线粒体来源的ROS的关键作用。具体而言 目的2，新型NRF2激活剂PB125将在卧床5天期间使用。预计激活 PB125与Nrf2联合应用可恢复衰老相关的Nrf2信号通路的功能障碍 内源性抗氧化酶，反过来，将维持由停用诱导的氧化还原平衡。初级阶段 这两个目标的结果衡量标准是通过腿部被动运动来评估血管功能。 (PLM)。次级结果测量将评估氧化应激对观察到的变化的贡献 在卧床前和卧床后血管和骨骼肌功能，将包括直接测量游离 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， 组织和系统水平，肌肉质量和力量的变化，以及肌肉蛋白质和基因的变化 在停用过程中可能与蛋白质分解和萎缩有机械联系的表达。