Determinants of 5 Year Progression of Muscle Dysfunction and Inactivity in COPDGene Participants.

COPDGene 参与者肌肉功能障碍和不活动 5 年进展的决定因素。

基本信息

批准号：
10552666
负责人：
Alessandra Adami
金额：
$ 37.79万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10552666
关键词：
Accelerometer Age American Ancillary Study Behavioral Biopsy Biopsy Specimen Body Composition Cardiovascular Diseases Cause of Death Cessation of life Characteristics Chronic Chronic Disease Chronic Obstructive Pulmonary Disease Clinical DNA DNA Methylation Data Diabetes Mellitus Diffusion Disease Disease Outcome Dual-Energy X-Ray Absorptiometry Enrollment Epigenetic Process Etiology Exercise Tolerance Exertion Exposure to Fluorometry Functional disorder Gases Gene Expression Genes Genetic Genetic Predisposition to Disease Genomics Health Hospitalization Hospitals Impairment Individual Inflammation Irritants Knowledge Light Lower Extremity Lung Lung diseases Measurement Measures Mediating Mediator Metabolic acidosis Methods Mitochondria Modification Muscle Muscle Mitochondria Muscle function Muscular Atrophy Nature Nuclear Obesity Outcome Parents Participant Patients Pharmaceutical Preparations Physical activity Predictive Factor Production Prognosis Pulmonary Emphysema Pulmonary Inflammation Quality of life RNA Resolution Risk Severities Shortness of Breath Skeletal Muscle Small RNA Smoker Smoking Spirometry Structure of parenchyma of lung Survival Rate Time Untranslated RNA Visit Work airway inflammation cigarette smoke cohort comorbidity deep sequencing disease diagnosis effective therapy epigenomics exercise capacity exercise intolerance exercise training follow-up functional decline gene discovery gene network genetic variant impaired capacity methylome mitochondrial dysfunction mitochondrial genome mortality muscle form never smoker novel therapeutic intervention physical inactivity predictive modeling premature prevent programs pulmonary function pulmonary rehabilitation quadriceps muscle reduce symptoms sedentary lifestyle symptomatic improvement transcriptome sequencing transcriptomics

项目摘要

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is destruction of lung tissue and/or thickening of lung airways. It is the fourth leading cause of death in the USA. COPD is progressive and characterized by chronic inflammation and shortness of breath on exertion, which leads to physical inactivity and skeletal muscle dysfunction. Survival rate in COPD is more closely associated with exercise capacity than the severity of lung disease. A key determinant of exercise capacity is the ability of skeletal muscle mitochondria to sustain cellular energy delivery (termed, oxidative capacity). We recently applied a noninvasive near-infrared light-based method to assess muscle oxidative capacity in 245 smokers with and without COPD: the COPDGene ancillary Muscle Health Study. We showed that severe COPD patients have a 40% lower muscle oxidative capacity than smokers or never smokers with normal lung function. Yet, many questions remain about characteristics and mechanisms behind the loss of muscle oxidative capacity in COPD. The current proposal will follow-up with 200 of the Muscle Health Study participants to determine for the first time the rate of decline in lower limb skeletal muscle oxidative capacity over 5 years. Using the individual genetics, triaxial accelerometer measured daily physical activity, body composition measured by DXA, and 808 other clinical variables collected in the COPDGene parent study, we will identify clinical, behavioral and genetic variables that associate with the 5-year decline in skeletal muscle oxidative capacity. In addition, quadriceps muscle biopsy samples from 20 COPD patients with the fastest decline and 20 with the slowest decline in muscle oxidative capacity, identified by the near-infrared based noninvasive assessment, will be used to discover how gene expression is altered by the disease. DNA methylation and expression of small and large RNAs, including small non-coding RNAs from the mitochondrial genome (mitosRNAs), will be probed. These highly specific approaches will provide a detailed profile of mitochondrial and nuclear genes and/or gene networks underlying the causes of derangements in the lower limb skeletal muscles of COPD patients. The decline in muscle oxidative capacity impairs exercise tolerance and predisposes patients to chronic diseases such as cardiovascular disease, diabetes and obesity, each of which increases risk of premature death. The current proposal will be the first to determine how loss of muscle oxidative capacity progresses in COPD, and answer fundamental questions about the nature of the associations among mitochondrial dysfunction, sedentary lifestyle and poor outcomes in COPD patients. Our findings will guide efforts to create new therapeutic strategies to prevent skeletal muscle dysfunction, increase autonomy, hospital free survival and quality-of-life in COPD.

项目摘要慢性阻塞性肺疾病（COPD）是肺组织的破坏和/或肺气道增厚。它是美国第四大死亡原因。 COPD是渐进的，以慢性炎症为特征劳累上的呼吸急促，这导致身体不活跃和骨骼肌肉功能障碍。生存与肺部疾病的严重程度相比，COPD的速率与运动能力更紧密相关。钥匙运动能力的决定因素是骨骼肌线粒体维持细胞能量的能力（称为氧化能力）。我们最近应用了一种非侵入性近红外光方法来评估有和没有COPD的245名吸烟者的肌肉氧化能力：COPDGENE辅助肌肉健康学习。我们表明，严重的COPD患者的肌肉氧化能力比吸烟者低40％或永远不要吸烟者具有正常的肺功能。然而，关于特征和机制仍然存在许多问题 COPD中肌肉氧化能力的丧失背后。当前的提案将跟进200个肌肉卫生研究参与者首次确定下肢骨骼肌氧化的率下降率能力超过5年。使用单个遗传学，三轴加速度计测量了每日体育锻炼，身体由DXA测量的组成，以及在Copdgene父母研究中收集的808个其他临床变量，我们将确定与骨骼肌5年下降相关的临床，行为和遗传变量氧化能力。此外，来自20例COPD患者的股四头肌活检样本下降，肌肉氧化能力下降最慢，近红外氧化能力下降最慢。非侵入性评估将用于发现基因表达如何被疾病改变。脱氧核糖核酸小和大RNA的甲基化和表达，包括线粒体的小非编码RNA 将探测基因组（mitosrnas）。这些高度特定的方法将提供详细的概况线粒体和核基因和/或基因网络是下肢造成扰动原因的基因网络 COPD患者的骨骼肌。肌肉氧化能力的下降会损害运动的耐受性和使患者容易患慢性疾病，例如心血管疾病，糖尿病和肥胖症增加死亡过早的风险。当前的建议将是第一个确定肌肉氧化损失的方法。能力在COPD中进展，并回答有关关联性质的基本问题 COPD患者的线粒体功能障碍，久坐的生活方式和差的结果。我们的发现将指导努力制定新的治疗策略，以防止骨骼肌功能障碍，增加自治权，医院 COPD中的免费生存和生活质量。