Nitric oxide coupling and BH4 availability roles in muscle dysfunction with COPD

一氧化氮偶联和 BH4 可用性在慢性阻塞性肺病 (COPD) 肌肉功能障碍中的作用

• 批准号: 9769837
• 负责人: GWENAEL LAYEC
• 金额: $ 24.62万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-04 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769837
• 关键词: Acute; Adult; Advocate; Aging; Airway Disease; Americas; Biological Availability; Blood Vessels; Blood flow; Cardiovascular Diseases; Cause of Death; Chronic; Chronic Obstructive Airway Disease; Clinical; Coupling; Development; Disease; Doppler Ultrasound; Elderly; Event; Exercise; Fiber; Functional disorder; Generations; Goals; In Vitro; Inflammation; Knowledge; Limb structure; Link; Lung; Lung diseases; Measurement; Metabolic; Metabolism; Methods; Mitochondria; Molecular; Morbidity - disease rate; Muscle; Muscle Development; Muscle function; Near-Infrared Spectroscopy; Nitric Oxide; Nitric Oxide Synthase; Nitrogen; Oxidative Stress; Oxygen; Patients; Perfusion; Peripheral; Phase; Phenotype; Play; Quality of life; Regulation; Respiration; Respiratory physiology; Role; Severities; Signaling Molecule; Skeletal Muscle; Spin Labels; Supplementation; Techniques; clinically relevant; cofactor; functional restoration; improved; in vivo; indexing; insight; interest; mortality; muscle metabolism; new therapeutic target; novel therapeutics; oxidative damage; prospective; tetrahydrobiopterin; vascular abnormality

DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in America, and, in 2011, 12.7 million US adults were estimated to have COPD. This disease is characterized by the progressive development of inflammation-induced airflow limitation, parenchymal destruction, and other systemic manifestations. Recognizing the limited advances in "lung focused" treatment options, it is of particular interest that skeletal muscle dysfunction is a frequent and clinically relevant systemic consequences of COPD that predicts morbidity and mortality, independently from the severity of lung function impairement. Several factors have been implicated in the development of muscle dysfunction with COPD, but oxidative stress has been suggested to play a major role. In other diseased states, also characterized by chronic oxidative stress (e.g. aging and cardiovascular disease), dysfunctional O2 transport and muscle metabolism in the periphery have been linked to both a lower nitric oxide (NO) bioavailability and nitric oxide synthase (NOS) uncoupling induced by a deficit in tetrahydrobiopterin (BH4). However, despite its potential as a novel target for therapeutic treatment, evidence of BH4 deficit-induced NOS uncoupling on the development of peripheral dysfunction with COPD is still lacking. Therefore, the goal of this project is to addres this gap in existing knowledge by elucidating the role of BH4 bioavailabiity and NOS coupling on peripheral O2 transport and muscle metabolism in patients suffering from COPD, with the prospective that BH4 supplemetation may be able to restore muscle function and improve the quality of life of these patients . Accordingly, during the K99 phase of this project, we will explre whether the severity of peripheral dysfunction assessed by several indices (perfusion/metabolism matching, limb blood flow, mitochondrial function in vivo and in permeabilized fibers, and contractile efficiency) during exercise in patients with COPD is related to the level of oxidative stress, as well as BH4 and NO bioavailability (Aim 1). We will then examine the effects of acute (Aim 2) and chronic (Aim 3) supplementations of BH4 on NOS coupling, the level of oxidative stress and NO bioavailability in the muscle and the vasculature, with the ultimate goal to restore skeletal muscle function and the functionnal capacity of these patients. To achieve these aims, we will use a comprehensive approach combining in vivo Near-Infrared Spectroscopy (NIRS), Doppler Ultrasound, Arterial Spin Labeling (ASL), and 31P-MRS measurements of O2 transport and muscle metabolism in exercising muscle, and in vitro methods utilizing molecular techniques to assess the level of oxidative stress, and permeabilized fibers to further interrogate mitochondrial respiration. At the conclusion of these studies, we will have expanded our knowledge of the mechanisms underlying muscle dysfunction in patients suffering from COPD, and, perhaps more important from a clinical perspective, provided insight into a potential novel therapeutic treatment for this disease.

描述（由申请人提供）：慢性阻塞性肺病 (COPD) 是美国第三大死因，2011 年，估计有 1,270 万美国成年人患有 COPD。该疾病的特征是炎症引起的气流受限、实质破坏和其他全身表现的逐渐发展。认识到“以肺为中心”的治疗方案进展有限，特别令人感兴趣的是，骨骼肌功能障碍是 COPD 的一种常见且具有临床相关性的系统性后果，可预测发病率和死亡率，与肺功能受损的严重程度无关。慢性阻塞性肺病（COPD）肌肉功能障碍的发生与多种因素有关，但氧化应激被认为起着主要作用。在其他以慢性氧化应激（例如衰老和心血管疾病）为特征的疾病状态中，外周 O2 运输和肌肉代谢功能障碍与四氢生物蝶呤 (BH4) 缺乏引起的一氧化氮 (NO) 生物利用度降低和一氧化氮合酶 (NOS) 解偶联有关。然而，尽管其具有作为治疗新靶标的潜力，但仍缺乏 BH4 缺陷诱导的 NOS 解偶联与 COPD 外周功能障碍发展的证据。因此，该项目的目标是通过阐明 BH4 生物利用度和 NOS 偶联对外周 O2 转运和 COPD 患者肌肉代谢的作用来弥补现有知识中的这一空白，并展望补充 BH4 可能能够恢复这些患者的肌肉功能并改善生活质量。因此，在本项目的K99阶段，我们将探讨COPD患者运动时通过多项指标（灌注/代谢匹配、肢体血流量、体内和透化纤维线粒体功能、收缩效率）评估的外周功能障碍的严重程度是否与氧化应激水平以及BH4和NO生物利用度相关（目标1）。然后，我们将检查急性（目标 2）和慢性（目标 3）补充 BH4 对 NOS 偶联、氧化应激水平以及肌肉和脉管系统中 NO 生物利用度的影响，最终目标是恢复这些患者的骨骼肌功能和功能能力。为了实现这些目标，我们将使用一种综合方法，结合体内近红外光谱 (NIRS)、多普勒超声、动脉自旋标记 (ASL) 和 31P-MRS 测量运动肌肉中的 O2 转运和肌肉代谢，以及利用分子技术评估氧化应激水平的体外方法，以及利用透化纤维进一步询问 线粒体呼吸。在这些研究结束时，我们将扩展对慢性阻塞性肺病患者肌肉功能障碍机制的了解，并且从临床角度来看，也许更重要的是，为这种疾病的潜在新型治疗方法提供了见解。