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Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis

Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of...

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Autores principales: Leitner, Brooks P., Lee, Won D., Zhu, Wanling, Zhang, Xinyi, Gaspar, Rafael C., Li, Zongyu, Rabinowitz, Joshua D., Perry, Rachel J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10325078/
https://www.ncbi.nlm.nih.gov/pubmed/37410734
http://dx.doi.org/10.1371/journal.pone.0286525
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author Leitner, Brooks P.
Lee, Won D.
Zhu, Wanling
Zhang, Xinyi
Gaspar, Rafael C.
Li, Zongyu
Rabinowitz, Joshua D.
Perry, Rachel J.
author_facet Leitner, Brooks P.
Lee, Won D.
Zhu, Wanling
Zhang, Xinyi
Gaspar, Rafael C.
Li, Zongyu
Rabinowitz, Joshua D.
Perry, Rachel J.
author_sort Leitner, Brooks P.
collection PubMed
description Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and (13)C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine’s contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine’s contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis.
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spelling pubmed-103250782023-07-07 Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis Leitner, Brooks P. Lee, Won D. Zhu, Wanling Zhang, Xinyi Gaspar, Rafael C. Li, Zongyu Rabinowitz, Joshua D. Perry, Rachel J. PLoS One Research Article Reprogramming metabolism is of great therapeutic interest for reducing morbidity and mortality during sepsis-induced critical illness. Disappointing results from randomized controlled trials targeting glutamine and antioxidant metabolism in patients with sepsis have begged a deeper understanding of the tissue-specific metabolic response to sepsis. The current study sought to fill this gap. We analyzed skeletal muscle transcriptomics of critically ill patients, versus elective surgical controls, which revealed reduced expression of genes involved in mitochondrial metabolism and electron transport, with increases in glutathione cycling, glutamine, branched chain, and aromatic amino acid transport. We then performed untargeted metabolomics and (13)C isotope tracing to analyze systemic and tissue specific metabolic phenotyping in a murine polymicrobial sepsis model. We found an increased number of correlations between the metabolomes of liver, kidney, and spleen, with loss of correlations between the heart and quadriceps and all other organs, pointing to a shared metabolic signature within vital abdominal organs, and unique metabolic signatures for muscles during sepsis. A lowered GSH:GSSG and elevated AMP:ATP ratio in the liver underlie the significant upregulation of isotopically labeled glutamine’s contribution to TCA cycle anaplerosis and glutamine-derived glutathione biosynthesis; meanwhile, the skeletal muscle and spleen were the only organs where glutamine’s contribution to the TCA cycle was significantly suppressed. These results highlight tissue-specific mitochondrial reprogramming to support liver energetic demands and antioxidant synthesis, rather than global mitochondrial dysfunction, as a metabolic consequence of sepsis. Public Library of Science 2023-07-06 /pmc/articles/PMC10325078/ /pubmed/37410734 http://dx.doi.org/10.1371/journal.pone.0286525 Text en © 2023 Leitner et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Leitner, Brooks P.
Lee, Won D.
Zhu, Wanling
Zhang, Xinyi
Gaspar, Rafael C.
Li, Zongyu
Rabinowitz, Joshua D.
Perry, Rachel J.
Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
title Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
title_full Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
title_fullStr Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
title_full_unstemmed Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
title_short Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
title_sort tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10325078/
https://www.ncbi.nlm.nih.gov/pubmed/37410734
http://dx.doi.org/10.1371/journal.pone.0286525
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