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.