Tissue-specific reprogramming of glutamine metabolism maintains tolerance to sepsis

• Published in: PloS one Vol. 18; no. 7; p. e0286525
• Main Authors: Leitner, Brooks P., Lee, Won D., Zhu, Wanling, Zhang, Xinyi, Gaspar, Rafael C., Li, Zongyu, Rabinowitz, Joshua D., Perry, Rachel J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.07.2023; Public Library of Science (PLoS)
• Subjects: Amino acids; Analysis; Antioxidants; Biology and Life Sciences; Biopsy; Biosynthesis; Care and treatment; Chain branching; Clinical trials; Correlation; Cytokines; Diagnosis; Electron transport; Fatty acids; Gene expression; Glutamine; Glutathione; Health aspects; Infection; Inflammation; Intensive care; Kidneys; Liver; Mass spectrometry; Medicine and Health Sciences; Metabolic response; Metabolism; Metabolites; Metabolomics; Mitochondria; Morbidity; Mortality; Muscles; Musculoskeletal system; Organs; Oxidation; Oxidative stress; Patients; Phenotyping; Physical Sciences; Physiological aspects; Plasma; Quadriceps muscle; Scientific imaging; Sepsis; Skeletal muscle; Spleen; Tissues; Transcriptomics; Tricarboxylic acid cycle; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0286525

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.