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Principal Investigator: Adolfo Ariel Jaitovich
Organization: ALBANY MEDICAL COLLEGE
Fiscal Year: 2024
Award: $544,301
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><5'-AMP-activated protein kinase><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><Acceleration><Activities of Daily Living><Activities of everyday life><Address><Anabolism><Animal Diseases><Animal Model><Animal Models and Related Studies><Animals><Assay><Attenuated><Bioassay><Biogenesis><Biological Assay><Blood><Blood Reticuloendothelial System><CO2><COPD><Carbon Dioxide><Carbonic Anhydride><Catabolism><Cell Body><Cell Respiration><Cells><Cellular Respiration><Cessation of life><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical><Complex><Data><Death><Dedications><Disease Outcome><Down-Regulation><Drug Modulation><Dysfunction><Emphysema><Environment><Event><Exercise><Exposure to><Fatigue><Fiber><Fumarate Reductase><Functional disorder><Gene Deletion><Generations><Genetic><Goals><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Hospital Admission><Hospitalization><Hypercapnia><Intermediary Metabolism><Knock-out><Knockout><LKB1><LKB1/STK11 Gene><Lack of Energy><Long-Term Effects><Longterm Effects><Lung Diseases><Measures><Mediating><Metabolic><Metabolic Processes><Metabolic Protein Degradation><Metabolic dysfunction><Metabolism><Mice><Mice Mammals><Mission><Mitochondria><Modeling><Molecular><Murine><Mus><Muscle><Muscle Atrophy><Muscle Cells><Muscle Disease><Muscle Disorders><Muscle Fibers><Muscle Tissue><Muscle Weakness><Muscle function><Muscular Atrophy><Muscular Diseases><Muscular Weakness><Myocytes><Myopathic Conditions><Myopathic Diseases and Syndromes><Myopathic disease or syndrome><Myopathy><Myotubes><NIH><National Institutes of Health><Origin of Life><Outcome><Oxidative Stress><Oxygen Consumption><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phenotype><Physiopathology><Process><Property><Protein Turnover><Proteins><Proteomics><Public Health><Publishing><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Emphysema><QOL><Quality of life><Recovery><Regulation><Regulatory Protein Degradation><Reporting><Research><Respiration><Rhabdomyocyte><Role><STK11><STK11 gene><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Succinate Dehydrogenase><Succinic Dehydrogenase><Succinic Oxidase><Toxic effect><Toxicities><Transgenic Animals><United States National Institutes of Health><Voluntary Muscle><aerobic metabolism><aerobic respiration><attenuate><attenuates><biological adaptation to stress><biosynthesis><carbon dioxide retention><chronic obstructive pulmonary disorder><coping><daily living function><daily living functionality><disability><disease model><disease of the lung><disorder model><disorder of the lung><elevated carbon dioxide><emphysematous><experiment><experimental research><experimental study><experiments><fumarate hydrogenase><functional ability><functional capacity><gain of function><gene deletion mutation><hydroxymethylglutaryl-CoA-reductase kinase><hypercarbia><improved><increased level Carbon dioxide><liver kinase B1><loss of function><lung disorder><metabolic phenotype><metabotype><mitochondrial><model of animal><mortality><mouse model><murine model><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle wasting><muscular><muscular disorder><oxidative metabolism><pathophysiology><patient oriented outcomes><patient prognosis><prevent><preventing><protein degradation><protein metabolism><reaction; crisis><respiratory><respiratory mechanism><social role><stress response><stress; reaction>