Accelerated Metabolic Aging in Rheumatoid Arthritis Immune cells and Skeletal Muscle: A Pilot Study

类风湿关节炎免疫细胞和骨骼肌加速代谢老化：一项初步研究

• 批准号: 10026407
• 负责人: Brian James Andonian
• 金额: $ 16.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10026407
• 关键词: Age; Aging; Anti-Inflammatory Agents; Atherosclerosis; Autoimmune Diseases; Biological Assay; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Respiration; Cells; Cellular Metabolic Process; Cessation of life; Clinical; Clinical Research; Data; Development; Disease; Disease model; Elderly; Feasibility Studies; Foundations; Freezing; Future; Helper-Inducer T-Lymphocyte; Human; Immune; Impairment; Inflammation; Inflammatory; Insulin Resistance; Interval training; Intervention; Knowledge; Lead; Learning; Link; Measurement; Measures; Mentors; Metabolic; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Muscle; Muscle Fibers; Muscle Mitochondria; Near-Infrared Spectroscopy; Organ; Oxygen Consumption; Participant; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Physicians; Pilot Projects; Premature aging syndrome; Regulation; Research; Research Training; Respiratory physiology; Rheumatoid Arthritis; Risk; Sampling; Scientist; Skeletal Muscle; T-Lymphocyte; Testing; Tissues; Training; Training Programs; Translational Research; Work; aged; cardiometabolic risk; cardiometabolism; career; cohort; comorbidity; design; disability; exercise program; exercise training; improved; lifestyle intervention; macrophage; mitochondrial dysfunction; mortality; overtreatment; peripheral blood; prospective; repository; response; rheumatologist; sarcopenia; sarcopenic obesity; seropositive; sex

Project Summary/Abstract Rheumatoid arthritis (RA) is a model disease for studying premature aging. Despite revolutionary improvements in anti-inflammatory treatments over the past few decades, persons with RA continue to suffer from early aging-associated metabolic comorbidities, evidenced by an increased risk of sarcopenic obesity, insulin resistance, atherosclerosis and mortality. RA and aged immune cells have abnormal metabolic and mitochondrial function, which coincide with immune dysregulation. Skeletal muscle in both RA and aging is also marked by altered metabolism. In the proposed study, I will investigate whether dysfunction of mitochondria, the cellular metabolic “engine,” connect RA peripheral helper T-cells, inflammatory macrophages and skeletal muscle abnormalities. My objectives for this pilot, feasibility study are twofold: 1) to determine whether RA peripheral T cell, macrophage and skeletal muscle mitochondrial function abnormalities are associated and 2) to determine the effects of exercise training on RA peripheral immune cell and skeletal muscle mitochondria. I hypothesize that 1) metabolic alterations in RA immune cells and skeletal muscle are interconnected, driven either by interorgan crosstalk or by master metabolic regulation; and 2) that interventions targeting global mitochondrial dysfunction will improve both cardiometabolic comorbidities and autoimmune disease in RA. As a first step to test my hypotheses in this pilot study, I will compare peripheral naïve CD4+ T cell and inflammatory macrophage mitochondrial respiratory function to permeabilized muscle fiber mitochondrial respiratory function and near-infrared spectroscopy muscle oxidative capacity measurements in older persons (ages 55-85 years) with seropositive or erosive RA (n=10). I will also compare these immune cell and muscle mitochondrial function assessments in RA to age-, sex-, BMI-matched healthy controls (n=10). Additionally, using existing frozen samples, I will assess mitochondrial function responses to exercise training from 12 persons (age range 52-80) with RA that underwent a 10-week high intensity interval training exercise program. I will then use stored baseline and post-training immune cells and muscle tissue for mitochondrial function assessments in peripheral blood mononuclear cells and skeletal muscle. I expect that findings from this pilot study will provide a framework for my future research on interorgan metabolic regulation and mitochondrial adaptation to exercise training in both aging and RA. My results promise to increase scientific knowledge of the connections between two main “pillars of aging”: inflammation and metabolism.

项目总结/摘要 类风湿性关节炎（RA）是研究早衰的模型疾病。尽管革命 尽管在过去几十年中抗炎治疗的改善，RA患者继续遭受 从早期衰老相关的代谢合并症，证明了减少肌肉的肥胖的风险增加， 胰岛素抵抗、动脉粥样硬化和死亡率。类风湿关节炎和老年免疫细胞代谢异常， 线粒体功能，这符合免疫失调。骨骼肌在RA和老化都是 新陈代谢也发生了改变在拟议的研究中，我将调查是否功能障碍， 线粒体，细胞代谢“引擎”，连接RA外周辅助T细胞，炎症巨噬细胞， 和骨骼肌异常我进行这项试点可行性研究的目的有两个：1）确定 RA外周血T细胞、巨噬细胞和骨骼肌线粒体功能异常是否 2）研究运动训练对RA患者外周血免疫细胞和骨骼肌的影响， 肌肉线粒体我假设1）RA免疫细胞和骨骼肌的代谢改变是 相互关联，由器官间串扰或主代谢调节驱动;以及2） 针对整体线粒体功能障碍的干预将改善心脏代谢合并症， 自身免疫性疾病 在这项初步研究中，作为检验我的假设的第一步，我将比较外周血幼稚CD 4 + T细胞和 炎症巨噬细胞线粒体呼吸功能对透化肌纤维线粒体 老年人呼吸功能和近红外光谱肌肉氧化能力测量 (ages 55-85岁）血清阳性或糜烂性RA（n=10）。我也会比较这些免疫细胞和肌肉 RA中的线粒体功能评估与年龄、性别、BMI匹配的健康对照（n=10）。此外，本发明还 使用现有的冷冻样本，我将评估线粒体功能对运动训练的反应， RA患者（年龄范围52-80岁）接受了为期10周的高强度间歇训练运动计划。 然后，我将使用存储的基线和训练后的免疫细胞和肌肉组织进行线粒体功能 在外周血单核细胞和骨骼肌中的评估。我希望这个试点的结果 本研究将为我今后在器官间代谢调控和线粒体方面的研究提供一个框架 老年人和类风湿关节炎患者对运动训练的适应性。我的研究结果有望增加科学知识， 两个主要的“衰老支柱”之间的联系：炎症和新陈代谢。