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

急性住院期间的废用与功能缺陷、再入院、恢复受损、 并增加死亡率。老年人由于功能（血管和骨骼肌）特别脆弱 线粒体功能障碍）和结构（肌肉质量和力量损失）缺陷表现为 老化过程的结果。在老年人中，不用时会加速衰退，进一步消耗 生理和功能储备能力已经减弱。目前，以骨骼肌为中心 防止萎缩和力量损失的策略是无效的，并且导致的机制 加速损失尚不清楚，但似乎与氧化应激有关。因此，识别 机制并制定有效的策略来减轻血管和骨骼肌功能的损失， 与流动性、疾病进展和健康密切相关的系统对于延缓疾病的发生至关重要 残疾并维护老年人的健康。我们的中心假设是氧化应激会引发 废用期间血管和骨骼肌功能加速下降。两个新颖且根本的 提出了减少氧化应激的独特方法，包括： 1）线粒体靶向抗氧化剂 （MITO-AO；目标 1）和 2）核因子类红细胞 2 2 (Nrf2) 激活剂 PB125（目标 2）。共有72名健康人 老年男性和女性（> 65 岁）将被随机分为 3 组；对照、MITO-AO 和 PB125。五 卧床休息几天，这是一种模仿急性住院的废用模型，将用于引起氧化应激和 血管和骨骼肌功能丧失。在具体目标 1 中，参与者将收到 MITO-AO（包括 米托醌）卧床休息5天。预计 MITO-AO 将减缓氧化应激的增加 通过限制线粒体衍生的活性氧（ROS）的产生，从而保护血管和 骨骼肌功能，从而揭示线粒体衍生的 ROS 的关键作用。在具体目标 2 中， 新型 Nrf2 激活剂 PB125 将在卧床休息 5 天期间施用。预计 Nrf2 的激活 与 PB125 一起使用将恢复 Nrf2 信号通路的与年龄相关的功能障碍，从而导致诱导 内源性抗氧化酶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。

Disuse during acute hospitalization is linked to functional deficiencies, hospital readmission, impaired recovery, and increased mortality. Older adults are particularly vulnerable 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. In older adults, accelerated declines occur during disuse further depleting an already diminished physiological and functional reserve capacity. Currently, skeletal muscle-centered strategies to prevent atrophy and losses in strength are ineffective and the mechanism(s) contributing to accelerated losses are unknown, but appear to be linked to oxidative stress. Therefore, identifying the mechanism(s) and developing effective strategies to mitigate 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. It is our central hypothesis that oxidative stress triggers the accelerated declines in vascular and skeletal muscle function during disuse. Two novel and fundamentally unique approaches to diminish oxidative stress are proposed including; 1) mitochondrial targeted antioxidants (MITO-AO; 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, MITO-AO, 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 MITO-AO (consisting of mitoquinone) during 5 days of bed rest. It is expected that MITO-AO 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 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 outcomes 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.