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

项目总结 慢性阻塞性肺疾病(COPD)是指肺组织的破坏和/或肺气道的增厚。它 是美国第四大死因。慢性阻塞性肺疾病是进行性的，以慢性炎症为特征 以及运动时呼吸短促，这会导致身体不活动和骨骼肌功能障碍。生死存亡 与肺部疾病的严重程度相比，慢性阻塞性肺疾病的发病率与运动能力的关系更密切。一把钥匙 运动能力的决定因素是骨骼肌线粒体维持细胞能量输送的能力 (称为氧化能力)。我们最近应用了一种基于近红外光的非侵入性方法来评估 245名患有和不患有COPD的吸烟者的肌肉氧化能力：COPD基因辅助肌肉健康 学习。我们发现，重度COPD患者的肌肉氧化能力比吸烟者或 肺功能正常的人从不吸烟。然而，许多关于特征和机制的问题仍然存在。 慢性阻塞性肺病患者肌肉氧化能力丧失的原因。目前的提议将对200名肌肉进行后续治疗 健康研究参与者首次确定下肢骨骼肌氧化下降率 产能在5年以上。利用个体遗传学，三轴加速度计测量日常体力活动、身体 由DXA测量的成分，以及在COPD基因亲本研究中收集的808个其他临床变量，我们 将确定与骨骼肌5年来下降相关的临床、行为和遗传变量 氧化能力。此外，从20名COPD患者的股四头肌活检样本中 下降和20的肌肉氧化能力下降最慢，由近红外基 非侵入性评估，将被用于发现疾病是如何改变基因表达的。脱氧核糖核酸 小RNA和大RNA的甲基化和表达，包括来自线粒体的非编码小RNA 基因组(MitosRNAs)，将被探测。这些高度具体的方法将提供关于 线粒体和核基因和/或基因网络是导致肢体紊乱的原因 慢性阻塞性肺疾病患者的骨骼肌。肌肉氧化能力的下降会损害运动耐量和 使患者容易患慢性疾病，如心血管疾病、糖尿病和肥胖症，其中每一种 增加过早死亡的风险。目前的提案将第一次确定肌肉氧化损失是如何 慢性阻塞性肺病方面的能力进展，并回答关于以下方面联系性质的基本问题 慢性阻塞性肺疾病患者线粒体功能障碍、久坐不动的生活方式和不良预后。我们的发现将指导 努力创造新的治疗策略来预防骨骼肌功能障碍，增加自主性，医院 慢性阻塞性肺疾病患者的自由生存和生活质量。

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.