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: 10673189
• 负责人: Joel Douglas Trinity
• 金额: $ 58.05万
• 依托单位: UNIVERSITY OF UTAH
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10673189
• 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; Outcome; Outcome Measure; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Oxygen; Participant; Pathway interactions; Patients; Physiological; Process; Production; Proteolysis; Randomized; Reactive Oxygen Species; Recovery; Role; Serious Adverse Event; Signal Pathway; Skeletal Muscle; System; Testing; Tissues; Vascular Diseases; Vascular System; 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 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.

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.

项目成果

Targeting Endogenous Antioxidant Capacity to Prevent Vascular Dysfunction Induced by Limb Immobilization.

针对内源性抗氧化能力，预防肢体固定引起的血管功能障碍。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Fermoyle,Caitlin;Lewis,Matthew;Craig,Jesse;McKenzie,Alec;Richardson,Russell;Trinity,Joel
• 通讯作者: Trinity,Joel