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

项目摘要/摘要 类风湿关节炎(RA)是一种研究早衰的模型疾病。尽管是革命性的 消炎治疗的改进在过去的几十年里，类风湿关节炎患者继续遭受 早期与衰老相关的代谢合并症，表现为骨质源性肥胖症风险增加， 胰岛素抵抗、动脉粥样硬化和死亡率。RA和衰老的免疫细胞代谢异常， 线粒体功能，这与免疫失调是一致的。骨骼肌在RA和衰老中都是 也以新陈代谢改变为特征。在拟议的研究中，我将调查是否存在功能障碍 线粒体，细胞代谢的引擎，连接RA外周辅助T细胞，炎性巨噬细胞 和骨骼肌异常。我对这项试点和可行性研究的目标有两个：1)确定 RA患者外周血T细胞、巨噬细胞和骨骼肌线粒体功能是否异常 2)确定运动训练对RA外周免疫细胞和骨骼的影响 肌肉线粒体。我假设1)RA免疫细胞和骨骼肌的代谢变化 相互关联，要么由器官间串扰驱动，要么由主代谢调节驱动；以及2) 针对全球线粒体功能障碍的干预将改善心脏代谢合并症和 类风湿关节炎中的自身免疫性疾病。 作为在这项初步研究中检验我的假设的第一步，我将比较外周血中幼稚的CD4+T细胞和 炎性巨噬细胞线粒体对通透性肌纤维线粒体的呼吸功能 老年人呼吸功能和近红外光谱肌肉氧化能力的测定 年龄55~85岁，血清阳性或侵袭性类风湿关节炎(n=10)。我还会比较这些免疫细胞和肌肉 对年龄、性别、体重指数匹配的健康对照组(n=10)进行类风湿关节炎患者的线粒体功能评估。另外， 利用现有的冰冻样本，我将从12岁起评估线粒体对运动训练的功能反应 接受10周高强度间歇训练锻炼计划的类风湿关节炎患者(年龄范围52-80岁)。 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来检测线粒体功能 外周血、单个核细胞和骨骼肌的检测。我希望这次试行的结果 这项研究将为我未来对器官间代谢调节和线粒体的研究提供一个框架 老年和类风湿性关节炎患者对运动训练的适应。我的研究结果有望增加对 衰老的两个主要支柱之间的联系：炎症和新陈代谢。

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.