Mechanisms and clinical relevance of hypercapnia-induced skeletal muscle atrophy in Chronic Obstructive Pulmonary Disease (COPD)

慢性阻塞性肺疾病（COPD）中高碳酸血症引起的骨骼肌萎缩的机制和临床相关性

• 批准号: 10395661
• 负责人: Adolfo Ariel Jaitovich
• 金额: $ 6.18万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2022-03-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395661
• 关键词: Attenuated; Biogenesis; Blood; Carbon Dioxide; Cells; Chronic Obstructive Airway Disease; Clinical; Disease Outcome; Exposure to; Fiber; Functional disorder; Hypercapnia; Knock-out; Lead; Long-Term Effects; Metabolism; Mission; Mitochondria; Muscle; Myopathy; Outcome; Patients; Pharmaceutical Preparations; Process; Prognosis; Public Health; Pulmonary Emphysema; Quality of life; Research; Respiration; STK11 gene; Skeletal Muscle; United States National Institutes of Health; clinically relevant; mortality; prevent; protein degradation; protein metabolism; skeletal muscle wasting

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 extension proposes to investigate the contribution of dysregulated cellular metabolism to the pathophysiology of CO2-retaining COPD. The hypothesis that supports this application is that hypercapnia attenuates COPD-induced reduced fiber respiration via LKB1-AMPK-driven mitochondrial biogenesis. To investigate that hypothesis, we will determine 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 exposed to elevated CO2. 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 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。 目前的扩展建议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。 该应用是高碳酸血症通过 LKB1-AMPK 驱动减弱 COPD 引起的纤维呼吸减少 为了研究这一假设，我们将确定其具体机制。 调节 CO2 驱动的功能失调代谢，因为 LKB1/AMPK 控制 CO2 感应和蛋白质周转。 骨骼肌、高碳酸血症对代谢的影响将通过 LKB1 敲除细胞暴露于 这项研究与现状相去甚远，重点关注的是 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 AMPK 是识别 COPD 肌肉呼吸和功能的主要参与者。