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

Award Number: R01HL160661
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $492,774 )
2025	2025	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Lung Diseases Research	000	4	11/21/2024	NON-COMPETING CONTINUATION	$492,774
														Subtotal = $492,774

Issue Date FY: 2024 ( Subtotal = $544,301 )
2024	2024	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Lung Diseases Research	000	3	11/22/2023	NON-COMPETING CONTINUATION	$499,870
2024	2024	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE # A34	ALBANY	NY	12208	ALBANY	USA	Lung Diseases Research	001	3	6/13/2024	NON-COMPETING CONTINUATION	$44,431
														Subtotal = $544,301

Issue Date FY: 2023 ( Subtotal = $563,067 )
2023	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Lung Diseases Research	000	2	11/9/2022	NON-COMPETING CONTINUATION	$506,761
2023	2023	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Lung Diseases Research	001	2	3/21/2023	NON-COMPETING CONTINUATION	$56,306
														Subtotal = $563,067

Issue Date FY: 2022 ( Subtotal = $570,500 )
2022	2022	ALBANY MEDICAL COLLEGE	47 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Lung Diseases Research	000	1	12/10/2021	NEW	$570,500
														Subtotal = $570,500

Grand Total All Awards = $2,170,642

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

Award Number: R01HL160661

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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