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

> **NIH NIH R01** · ALBANY MEDICAL COLLEGE · 2024 · $544,301

## Abstract

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.

## Key facts

- **NIH application ID:** 10738267
- **Project number:** 5R01HL160661-03
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** Adolfo Ariel Jaitovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $544,301
- **Award type:** 5
- **Project period:** 2021-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10738267

## Citation

> US National Institutes of Health, RePORTER application 10738267, Metabolic regulation of hypercapnic chronic obstructive pulmonary disease (COPD)-driven skeletal muscle dysfunction (5R01HL160661-03). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10738267. Licensed CC0.

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