Metabolic regulation of hypercapnic chronic obstructive pulmonary disease (COPD)-driven skeletal muscle dysfunction

项目摘要：慢性阻塞性肺疾病(COPD)/肺气肿患者常 出现运动肌肉功能障碍，这与较差的临床结果相关，包括 死亡率。血液中二氧化碳滞留或高碳酸血症在这些患者中也很常见，而且与 死亡率更高。调控这些过程的机制目前尚不清楚，现有的 在这种情况下，治疗对存活率没有影响。因此，了解控制二氧化碳的机制-- 保留COPD导致的肌肉功能障碍有助于制定预防和扭转这种情况的策略， 这些患者的生存和生活质量可能会受益。慢性阻塞性肺疾病患者的肌肉功能障碍与 蛋白质周转和代谢异常。本申请建议调查以下方面的贡献 细胞代谢紊乱对COPD的病理生理影响。支持这一假设的 这一应用是琥珀酸脱氢酶(SDH)/复合体-II亚单位-C下调代表 COPD驱动的骨骼肌功能障碍的基础事件，导致ATP生成减少和更高 高碳酸血症通过LKB1-AMPK驱动的线粒体生物发生来减弱这一过程。至 调查这一假说，第一个目的是致力于研究SDHC下调在COPD中的作用 使用我们最近发表的COPD驱动的骨骼肌功能障碍的动物模型的肌病。遗传 SDHC的恢复将允许功能获得解决导致代谢功能障碍的机制 慢性阻塞性肺疾病的肌肉。该提案的第二个目标将调查监管二氧化碳的具体机制- 导致新陈代谢失调。当LKB1/AMPK控制骨骼肌中的二氧化碳感知和蛋白质周转时， 高碳酸血症对代谢的影响将通过LKB1基因敲除细胞和暴露于 二氧化碳浓度升高。然后，我们将在单一型号上混合COPD和二氧化碳，并使用两个 转基因动物。这项研究通过将重点放在 代谢对慢性阻塞性肺疾病引起的肌肉功能障碍的长期影响的贡献，特别是通过 确定SDHC和AMPK是COPD肌肉呼吸和功能的主要参与者。

Project Summary: Patients with chronic obstructive pulmonary disease (COPD)/pulmonary emphysema often develop locomotor muscle dysfunction, which is associated with worse clinical outcomes including higher mortality. Retention of CO2 in the blood, or hypercapnia, is also frequent in these patients and similarly associated with higher mortality. The mechanisms that regulate these processes are currently unknown, and the available treatments have no effects on survival in this setting. Therefore, understanding the mechanisms controlling CO2- retaining COPD-driven muscle dysfunction could help develop strategies to prevent and reverse that, with potentially survival and quality of life benefits for these patients. Muscle dysfunction in COPD is associated with abnormal protein turnover and metabolism. The present application proposes to investigate the contribution of dysregulated cellular metabolism to the pathophysiology of CO2-retaining COPD. The hypothesis that supports this application is that succinate dehydrogenase (SDH)/complex-II subunit-C downregulation represents a fundamental event in COPD-driven skeletal muscle dysfunction, causing reduced ATP-generation and higher fatigability; and that hypercapnia attenuates this process via LKB1-AMPK-driven mitochondrial biogenesis. To investigate that hypothesis, the first aim is dedicated to studying the role of SDHC downregulation in COPD myopathy using an animal model of COPD-driven skeletal muscle dysfunction we recently published. Genetic restitution of SDHC will allow gain-of-function to address the mechanisms leading to metabolic dysfunction in COPD muscles. The second aim of the proposal will investigate the specific mechanisms that regulate CO2- driven dysfunctional metabolism. As LKB1/AMPK controls CO2 sensing and protein turnover in skeletal muscle, hypercapnia’s effect on metabolism will be investigated with LKB1 knockout cells and animals exposed to elevated CO2. We will then blend COPD and CO2 on a single model and perform loss of function with a double transgenic animal. This research represents a substantive departure from the status quo by focusing on the contribution of metabolism to the long-term effects of COPD-driven muscle dysfunction, and specifically by identifying SDHC and AMPK as major players COPD muscle respiration and function.