Skeletal muscle biology in rheumatoid arthritis

描述（由申请人提供）：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RA患者最常见的症状之一。虚弱会影响大多数主要肌肉群，并限制基本活动，如行走，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RA的姿势不稳定，使个体易受跌倒相关损伤，并显着降低整体生活质量。没有药物治疗RA相关的弱点，没有临床护理标准来解决这个衰弱的问题。该项目的目标是确定导致RA弱点的过程，并确定未来药物开发的生物靶点。RA患者的虚弱程度远远超过肌肉萎缩。因此，我们项目的重点是收缩功能的损失，反映了比力，即单位横截面积的力。我们的实验模型提出，RA增加肌肉暴露于促炎细胞因子，刺激产生一氧化氮（NO）衍生物和活性氧（ROS）的肌肉纤维。由此产生的氧化应激会抑制特异性力量并导致虚弱。干扰这一事件链的干预措施预计将保留特定的力量，对抗RA相关的弱点。我们将通过使用来自RA患者的肌肉和完善的RA小鼠模型（胶原诱导的关节炎，CIA）来测试该模型，以解决四个具体目标：具体目标1。鉴定RA诱导的虚弱所必需的细胞因子。具体目标2。确定类风湿关节炎引起的骨骼肌氧化剂产生的变化。具体目标3。明确RA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：风湿性关节炎（RA）是最常见的慢性炎症性疾病。肌无力是最普遍的症状之一，限制了日常生活的基本活动，使个体容易受到与跌倒有关的伤害，并降低了生活质量。该项目的目标是确定导致RA弱点的过程，并确定未来药物开发的生物靶点。

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.