Lipid hydroperoxides in sarcopenia and muscle wasting: mechanisms and intervention

脂质氢过氧化物在肌肉减少症和肌肉萎缩中的作用：机制和干预

基本信息

批准号：
10634499
负责人：
Jacob Levi Brown
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：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634499
关键词：
Acceleration Age Age Months Age Years Aging Animal Genetics Animal Model Arachidonate 15-Lipoxygenase Arachidonic Acids Atrophic Attenuated Body Composition Cessation of life Communication Cytoplasm Data Denervation Development Diabetes Mellitus Eicosanoids Electron Transport Enzymes Fiber Fracture Functional disorder Generations Genetic Genetic Induction Goals Hand Strength Health Health Expenditures Hindlimb Hydrogen Peroxide Intervention Knockout Mice Lipid Peroxidation Lipid Peroxides Lipids Maintenance Malnutrition Measures Mediator Membrane Mental Depression Mentors Mitochondria Modeling Morphology Motor Neurons Movement Mus Muscle Muscle Fibers Muscle Proteins Muscle function Muscular Atrophy Neuromuscular Junction Oxidative Stress Patients Permeability Phospholipase A2 Phospholipids Population Prevalence Production Protein Biosynthesis Proteins Psyche structure Quality of life Research Technics Risk Running Scientist Secondary to Skeletal Muscle Structure Superoxides Syndrome Testing Training Veterans adverse outcome age related age-related muscle loss aged catalase design effective intervention effective therapy experimental study falls gene therapy glutathione peroxidase healthspan improved meetings mitochondrial dysfunction mouse model muscle aging muscle degeneration muscle form muscle strength nerve supply novel overexpression oxidation pharmacologic physically handicapped protein biomarkers protein degradation reduced muscle mass response sarcopenia skeletal muscle wasting stable isotope symposium therapeutic target therapy design

项目摘要

SIGNIFICANCE TO VETERANS HEALTH: Two-thirds of all veterans are 55 years of age or older. Sarcopenia is a syndrome that effects approximately 25% of the U.S. population over the age of 70 characterized by progressive loss of skeletal muscle mass and strength with an increased risk of adverse outcomes such as physical disability, poor quality of life and even death. Further, the development of sarcopenia may lead to secondary health conditions such as disuse, malnutrition, falls, fractures and diabetes. In addition to the physical ailments that accompany patients that suffer from sarcopenia, sarcopenia contributes to over $18.5 billion dollars of total health care expenditures. The prevalence of sarcopenia is higher in subjects presenting another health condition than in healthy subjects including mental conditions such as depression that are common among veterans. There are currently no effective treatments for sarcopenia because underlying mechanisms are not fully elucidated. OBJECTIVES: The objective of this study is to test if denervation induced generation of lipid hydroperoxides (LOOHs), through the enzyme 12/15-Lipoxygenase (12/15-Lox) or through direct oxidation of lipids, leads to neuromuscular junction (NMJ) disruption and mitochondrial dysfunction that initiates muscle atrophy, muscle protein breakdown, and weakness. RESEARCH PLAN: In Specific Aim 1, I will test the effect of reducing LOOHs via treatment with the LOOH scavenger liproxstatin-1 on mitochondrial function, NMJ structure and function, protein turnover, and maintenance of muscle mass and function in aged mice. In Specific Aim 2, I will test the effect of muscle specific genetic deletion of 12/15-Lox, an enzyme that generates eicosanoids and oxylipins, on the maintenance of muscle mass and function in aged mice. Finally, in Specific Aim 3, I will test the effect of muscle specific overexpression of glutathione peroxidase 4 (GPx4), an enzyme that reduces LOOHs within membranes, on the maintenance of muscle mass and function in aged mice. We will use a combination of pharmacological approaches, genetic mouse models, and novel research techniques to test the central hypothesis. ANTICIPATED OUTCOMES: All of my Specific Aims focus on reducing skeletal muscle LOOHs (either enzymatically generated or direct oxidation of lipids) in response to age-related denervation. I hypothesize that my interventions will ameliorate skeletal muscle atrophy and dysfunction in hindlimb muscle from aged mice by reducing lipid peroxidation, improving mitochondrial function, reducing rates of protein degradation, and maintaining NMJ integrity. My preliminary data clearly shows that LOOH generation is elevated in aged muscle, and that LOOH generation is strongly correlated to muscle mass loss in models of denervation atrophy. For skeletal muscle mass loss to occur, rates of protein degradation have to be greater than rates of protein synthesis. Therefore, my interventions have to reduce rates of protein degradation and/or increase rates of protein synthesis in denervated muscle. There are multiple lines of evidence that shows mitochondrial health is important for the maintenance of skeletal muscle mass and function. My preliminary data shows that overexpression of GPx4 in a model of accelerated sarcopenia improves mitochondrial function, which may reduce muscle mass loss. Therefore, we hypothesize that reducing LOOHs in muscle will improve mitochondrial function in aged mice. Finally, denervation can propagate oxidative stress and NMJ disruption in surrounding fibers. We predict that reducing LOOHs in muscle will slow NMJ degradation of the surrounding fibers. TRAINING PLAN: My short-term goals are to delineate the mechanisms of LOOH driven sarcopenia and receive training in oxidative stress, aging, the use of stable isotopes, using genetic animal models, and scientific communication. I will receive this training through a combination of meetings with my mentoring team, conferences, presentation, formal courses, and performing experiments. The training plan I have outlined will allow me to achieve my long-term goal of becoming an independent VA scientist.

对退伍军人健康的重要性：三分之二的退伍军人年龄在 55 岁或以上。少肌症是一种影响大约 25% 70 岁以上美国人口的综合征，其特征是骨骼肌质量和力量逐渐丧失，不良后果的风险增加，例如身体残疾，生活质量差，甚至死亡。此外，肌肉减少症的发展可能导致次要健康状况，如废用、营养不良、跌倒、骨折和糖尿病。除了身体上的肌肉减少症患者伴随的疾病，肌肉减少症贡献了超过 185 亿美元医疗保健支出总额。存在其他健康状况的受试者中肌肉减少症的患病率较高与健康受试者相比，包括常见的精神状况，例如抑郁症退伍军人。目前还没有针对肌肉减少症的有效治疗方法，因为根本机制尚不明确。得到充分阐明。目的：本研究的目的是测试去神经支配是否会诱导脂质的产生氢过氧化物 (LOOH)，通过 12/15-脂氧合酶 (12/15-Lox) 或通过直接氧化脂质，导致神经肌肉接头（NMJ）破坏和线粒体功能障碍，从而启动肌肉萎缩、肌肉蛋白质分解和虚弱。研究计划：在具体目标1中，我将测试效果通过使用 LOOH 清除剂 liproxstatin-1 治疗来减少 LOOH 对线粒体功能的影响，NMJ 老年小鼠的结构和功能、蛋白质周转以及肌肉质量和功能的维持。具体来说目标 2，我将测试肌肉特异性基因删除 12/15-Lox（一种产生类二十烷酸的酶）的效果和氧脂素，用于维持老年小鼠的肌肉质量和功能。最后，在具体目标 3 中，我将测试肌肉特异性过表达谷胱甘肽过氧化物酶 4 (GPx4) 的效果，该酶可减少膜内的 LOOH 对维持老年小鼠的肌肉质量和功能有帮助。我们将使用一个结合药理学方法、遗传小鼠模型和新颖的研究技术来测试中心假设。预期结果：我所有的具体目标都集中在减少骨骼肌 LOOH（酶促产生或直接氧化脂质）响应与年龄相关的去神经支配。我假设我的干预措施将改善骨骼肌萎缩和后肢肌肉功能障碍通过减少脂质过氧化、改善线粒体功能、降低蛋白质比率而来自老年小鼠降解，并保持 NMJ 完整性。我的初步数据清楚地表明 LOOH 的产生量有所增加在衰老的肌肉中，LOOH 的产生与去神经模型中的肌肉质量损失密切相关萎缩。为了发生骨骼肌质量损失，蛋白质降解率必须大于蛋白质合成。因此，我的干预措施必须降低蛋白质降解率和/或提高蛋白质降解率失神经肌肉中蛋白质合成的影响。有多种证据表明线粒体健康对于维持骨骼肌质量和功能很重要。我的初步数据表明在加速肌肉减少症模型中过度表达 GPx4 可改善线粒体功能，这可能减少肌肉质量损失。因此，我们假设减少肌肉中的 LOOH 将改善线粒体在老年小鼠中发挥作用。最后，去神经可以在周围传播氧化应激和 NMJ 破坏。纤维。我们预测减少肌肉中的 LOOH 将减缓周围纤维的 NMJ 降解。培训计划：我的短期目标是描述 LOOH 驱动的肌肉减少症的机制并接受氧化应激、衰老、稳定同位素的使用、使用遗传动物模型和科学方面的培训沟通。我将通过与我的指导团队的会议相结合的方式接受培训，会议、演示、正式课程和进行实验。我概述的培训计划将让我能够实现成为一名独立的 VA 科学家的长期目标。