# Metabolic Energy Crisis Signature Predicts Quality of Life in Survivors of Acute Respiratory Failure

> **NIH NIH R21** · UNIVERSITY OF SOUTH ALABAMA · 2022 · $200,788

## Abstract

Project Summary/Abstract
Survivors of acute respiratory failure (ARF) often face a daunting return to normal life as they have significant
impairment of physical function. Over half of these patients are never able to return to work and often sustain
significant skeletal muscle loss. Reliable algorithms to predict long-term physical function are currently
unavailable. We previously described how metabolomics are predictive of acute outcomes in sepsis and ARF.
Many of these metabolomic changes are related to dysfunction of β-oxidation, the citric acid cycle (TAC) and
nicotinamide adenine dinucleotide (NADH) metabolism. Mitochondrial dysfunction is now considered to be a
major driver of sepsis outcomes and may play a role in sepsis-induced muscle dysfunction. Furthermore,
mitochondrial DNA (mtDNA) damage-associated molecular patterns (DAMPs) predicts patient outcomes in
critical illness and trauma. We have developed a novel and innovative RNA target-bait capture deep sequencing
and bioinformatics protocol for accurate quantitation and differentiation of mtDNA DAMPs and nuclear
mitochondrial pseudogenes We hypothesize that mtDNA damage-associated molecular patterns (DAMPs) or
metabolomic changes are reflective of mitochondrial-related bioenergetic status, and will also predict physical
function in six-month survivors of ARF. In support of this hypothesis, we found in a small pilot study that
mitochondrial related metabolites measured at patient discharge correlated with poor physical function in six-
month survivors of ARF. In this study, we propose to expand upon the metabolomic and mtDNA results by
leveraging patient data and plasma samples that were collected within the single center, randomized clinical trial
at Wake Forest Baptist Medical Center (TARGET; ClinicalTrials.gov Identifier: NCT00976833). This study was
designed to test if physical therapy initiated in the ICU reduced ICU length-of-stay and improved longterm quality-
of-life in survivors. In Aim 1, we will establish that increased concentrations of mtDNA DAMPs in cell-free plasma
predict physical function in survivors of ARF. Aim 2 will investigate the link between the concentration of
mitochondrial-related bioenergetics metabolites and the abundance of mtDNA DAMPs in cell-free plasma. The
results from this study will provide new pathophysiologic insight into the role of mtDNA DAMPs and
mitochondrial-associated metabolites in ARF-induced poor physical function. New pharamcological therapies
have the potential to improve physical function through improved mitochondrial function, biogenesis, and
reduction of mtDNA DAMPs, while NAD-derivatives or androgenic steroid repletion could improve physical
strength and function.

## Key facts

- **NIH application ID:** 10390486
- **Project number:** 5R21NR019338-02
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Raymond Julian Langley
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $200,788
- **Award type:** 5
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390486

## Citation

> US National Institutes of Health, RePORTER application 10390486, Metabolic Energy Crisis Signature Predicts Quality of Life in Survivors of Acute Respiratory Failure (5R21NR019338-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10390486. Licensed CC0.

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