Skeletal muscle biology in rheumatoid arthritis

描述(申请人提供)：类风湿性关节炎(RA)是最常见的慢性炎症性疾病，影响高达1%的人口。除了关节疼痛和僵硬，肌肉无力是类风湿关节炎患者最常见的症状之一。虚弱影响大多数主要肌肉群，并限制基本活动，如走路、坐着和从椅子上站起来、打开容器、穿衣和个人卫生。虚弱也会导致类风湿性关节炎的姿势不稳定，容易导致个人摔倒相关的伤害，并极大地降低整体生活质量。目前还没有针对RA相关虚弱的药物治疗，也没有临床护理标准来解决这一令人衰弱的问题。该项目的目标是定义导致类风湿性关节炎虚弱的过程，并为未来的药物开发确定生物靶点。在RA患者中，虚弱远远超过肌肉萎缩。因此，我们项目的重点是收缩功能的丧失，这是由比力反映的，即单位横截面面积的力。我们的实验模型认为，RA增加了肌肉对促炎细胞因子的暴露，这些细胞因子刺激肌肉纤维产生一氧化氮(NO)衍生物和活性氧(ROS)。由此产生的氧化应激抑制了特定的力量，导致虚弱。扰乱这一连串事件的干预措施预计将保留特定的力量，反对与RA相关的弱点。我们将通过使用RA患者的肌肉和已建立的RA(胶原诱导关节炎，CIA)小鼠模型来测试该模型，以解决四个特定目标：特定目标1.识别RA诱导的虚弱所必需的细胞因子。具体目的2.明确RA对骨骼肌氧化剂产生的影响。明确类风湿关节炎收缩功能障碍的细胞机制。具体目的4.探讨保留类风湿关节炎肌肉功能的治疗方法。 公共卫生相关性：类风湿性关节炎(RA)是最常见的慢性炎症性疾病。肌肉无力是最常见的症状之一，限制了日常生活的基本活动，使个人容易受到与跌倒相关的伤害，并降低了生活质量。该项目的目标是确定导致类风湿性关节炎虚弱的过程，并为未来的药物开发确定生物靶点。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, affecting up to 1% of the population. Beyond joint pain and stiffness, muscle weakness is among the most prevalent symptoms of RA patients. Weakness affects most major muscle groups and limits basic activities such as walking, sitting and rising from chairs, opening containers, dressing oneself, and personal hygiene. Weakness also contributes to postural instability in RA, predisposing individuals to fall-related injuries, and dramatically lessens the overall quality of life. There is no drug therapy for RA-related weakness, no clinical standard of care to address this debilitating problem. The goal of this project is to define processes that cause weakness in RA and identify biological targets for future drug development. Weakness far exceeds muscle atrophy in RA patients. Therefore, the focus of our project is loss of contractile function as reflected by specific force, i.e, force per cross-sectional area. Our experimental model proposes that RA increases muscle exposure to proinflammatory cytokines that stimulate production of nitric oxide (NO) derivatives and reactive oxygen species (ROS) by muscle fibers. The resulting oxidative stress depresses specific force and causes weakness. Interventions that disrupt this chain of events are expected to preserve specific force, opposing RA-related weakness. We will test this model by using muscles from RA patients and a well-established mouse model of RA (collagen-induced arthritis, CIA) to address four specific aims: Specific Aim 1. To identify cytokines essential for RA-induced weakness. Specific Aim 2. To define changes in skeletal muscle oxidant production caused by RA. Specific Aim 3. To define cellular mechanisms of contractile dysfunction in RA. Specific Aim 4.To test therapeutic approaches for preserving muscle function in RA. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is the most common chronic inflammatory disease. Muscle weakness is among the most prevalent symptoms, limiting basic activities of daily living, predisposing individuals to fall-related injuries, and lessening the quality of life. The goal of this project is to define the processes that cause weakness in RA and identify biological targets for future drug development.