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

高碳酸血症慢性阻塞性肺疾病（COPD）驱动的骨骼肌功能障碍的代谢调节

基本信息

批准号：
10539282
负责人：
Adolfo Ariel Jaitovich
金额：
$ 56.31万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539282
关键词：
5&apos -AMP-activated protein kinase Acceleration Activities of Daily Living Address Anabolism Animal Diseases Animal Model Animals Attenuated Biogenesis Biological Assay Blood Carbon Dioxide Catabolism Cell Respiration Cells Cessation of life Chronic Chronic Obstructive Pulmonary Disease Clinical Complex Data Dedications Disease Outcome Disease model Down-Regulation Drug Modulation Environment Event Exercise Exposure to Fatigue Fiber Functional disorder Gene Deletion Generations Genetic Goals Hospitalization Hypercapnia Knock-out Long-Term Effects Lung diseases Measures Mediating Metabolic Metabolic dysfunction Metabolism Mission Mitochondria Modeling Molecular Mus Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Myopathy Outcome Oxidative Stress Oxygen Consumption Patient-Focused Outcomes Patients Phenotype Process Property Proteins Proteomics Public Health Publishing Pulmonary Emphysema Quality of life Recovery Regulation Reporting Research Respiration Role STK11 gene Skeletal Muscle Succinate Dehydrogenase Toxic effect Transgenic Animals United States National Institutes of Health biological adaptation to stress coping disability experimental study gain of function improved loss of function metabolic phenotype mortality mouse model muscle form patient prognosis prevent protein degradation protein metabolism respiratory

项目摘要

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.

项目摘要：慢性阻塞性肺疾病（COPD）/肺气肿患者经常发展运动肌功能障碍，这与较差的临床结果相关，包括更高的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，并且具有类似的相关性。目前尚不清楚调节这些过程的机制和可用的机制。在这种情况下，治疗对生存没有影响，因此，了解控制 CO2- 的机制。保留慢性阻塞性肺病引起的肌肉功能障碍可能有助于制定预防和扭转这种情况的策略，这些患者的潜在生存和生活质量益处与慢性阻塞性肺病患者的肌肉功能障碍有关。本申请提出研究异常的蛋白质周转和代谢的贡献。细胞代谢失调与 CO2 滞留性 COPD 的病理生理学关系支持该假设。该应用是琥珀酸脱氢酶 (SDH)/复合体 II 亚基 C 下调代表 COPD 驱动的骨骼肌功能障碍的基本事件，导致 ATP 生成减少和更高疲劳；高碳酸血症通过 LKB1-AMPK 驱动的线粒体生物发生减弱了这一过程。研究该假设，第一个目标是致力于研究 SDHC 下调在 COPD 中的作用使用我们最近发表的慢性阻塞性肺病（COPD）驱动的骨骼肌功能障碍的动物模型来研究肌病。 SDHC 的恢复将允许功能获得，以解决导致代谢功能障碍的机制该提案的第二个目标是研究调节 CO2- 的具体机制。由于 LKB1/AMPK 控制骨骼肌中的 CO2 感应和蛋白质周转，高碳酸血症对新陈代谢的影响将通过 LKB1 敲除细胞和暴露于高碳酸血症的动物进行研究然后，我们将 COPD 和 CO2 混合在一个模型上，并用双模型执行功能丧失。这项研究代表了对现状的实质性偏离。新陈代谢对慢性阻塞性肺病（COPD）引起的肌肉功能障碍的长期影响的贡献，特别是通过 SDHC 和 AMPK 作为 COPD 肌肉呼吸和功能的主要参与者。