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.

项目总结：慢性阻塞性肺疾病（COPD）/肺气肿患者通常 发生运动肌肉功能障碍，这与更差的临床结局相关，包括更高的 mortality.血液中CO2潴留或高碳酸血症在这些患者中也是常见的，并且类似地与 死亡率更高。调节这些过程的机制目前尚不清楚， 在这种情况下，治疗对存活率没有影响。因此，了解控制CO2- 保留COPD驱动的肌肉功能障碍可能有助于制定预防和逆转这种情况的策略， 对这些患者的生存和生活质量有潜在的益处。COPD中的肌肉功能障碍与 蛋白质周转和代谢异常。本扩展建议调查的贡献 细胞代谢失调与CO2滞留型COPD的病理生理学之间的关系。支持这个假设的是 这种应用是高碳酸血症通过LKB 1-AMPK驱动的纤维呼吸减弱COPD诱导的减少的纤维呼吸， 线粒体生物发生为了研究这一假设，我们将确定特定的机制， 调节CO2驱动的功能失调的新陈代谢。由于LKB 1/AMPK控制CO2传感和蛋白质周转， 骨骼肌，高碳酸血症对代谢的影响将用LKB 1敲除细胞暴露于 CO2浓度升高。这项研究代表了一个实质性的偏离现状，重点放在 代谢对COPD驱动的肌肉功能障碍的长期影响的贡献，特别是 确定AMPK是COPD肌肉呼吸和功能的主要参与者。