title: Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary (13)C-glucose labeling metabolomics.
abstract: BACKGROUND
  Metabolic derangement is a key hallmark of major traumatic injury. The recent introduction of mass spectrometry-based metabolomics technologies in the field of trauma shed new light on metabolic aberrations in plasma that are triggered by trauma and hemorrhagic shock. Alteration in metabolites associated with catabolism, acidosis and hyperglycemia have been identified. However, the mechanisms underlying fluxes driving such metabolic adaptations remain elusive.
  
  
  METHODS
  A bolus of U-(13)C-glucose was injected in Sprague-Dawley rats at different time points. Plasma extracts were analyzed via ultra-high performance liquid chromatography-mass spectrometry to detect quantitative fluctuations in metabolite levels as well as to trace the distribution of heavy labeled carbon isotopologues.
  
  
  RESULTS
  Rats experiencing trauma did not show major plasma metabolic aberrations. However, trauma/hemorrhagic shock triggered severe metabolic derangement, resulting in increased glucose levels, lactate and carboxylic acid accumulation. Isotopologue distributions in late Krebs cycle metabolites (especially succinate) suggested a blockade at complex I and II of the electron transport chain, likely due to mitochondrial uncoupling. Urate increased after trauma and hemorrhage. Increased levels of unlabeled mannitol and citramalate, metabolites of potential bacterial origin, were also observed in trauma/hemorrhagic shock rats, but not trauma alone or controls.
  
  
  CONCLUSIONS
  These preliminary results are consistent with observations we have recently obtained in humans, and expand upon our early results on rodent models of trauma and hemorrhagic shock by providing the kinetics of glucose fluxes after trauma and hemorrhage. Despite the preliminary nature of this study, owing to the limited number of biological replicates, results highlight a role for shock, rather than trauma alone, in eliciting systemic metabolic aberrations. This study provides the foundation for tracing experiments in rat models of trauma. The goal is to improve our understanding of substrate specific metabolic derangements in trauma/hemorrhagic shock, so as to design resuscitative strategies tailored toward metabolic alterations and the severity of trauma.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, East 17th Ave, Aurora, CO, 12801, USA. angelo.dalessandro@ucdenver.edu.
authors.forename: Angelo
authors.initials: A
authors.lastname: D'Alessandro
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. anne.slaughter@ucdenver.edu.
authors.forename: Annie L
authors.initials: AL
authors.lastname: Slaughter
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. erik.peltz@ucdenver.edu.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Peltz
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. ernest.moore@dhha.org.|Denver Health Medical Center, Denver, CO, USA. ernest.moore@dhha.org.
authors.forename: Ernest E
authors.initials: EE
authors.lastname: Moore
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. christopher.silliman@ucdenver.edu.|Bonfils Blood Center, Denver, CO, USA. christopher.silliman@ucdenver.edu.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Silliman
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, East 17th Ave, Aurora, CO, 12801, USA. matthew.wither@ucdenver.edu.
authors.forename: Matthew
authors.initials: M
authors.lastname: Wither
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, East 17th Ave, Aurora, CO, 12801, USA. travis.nemkov@ucdenver.edu.
authors.forename: Travis
authors.initials: T
authors.lastname: Nemkov
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. anthony.bacon@ucdenver.edu.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Bacon
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. miguel.fragoso@ucdenver.edu.|Denver Health Medical Center, Denver, CO, USA. miguel.fragoso@ucdenver.edu.
authors.forename: Miguel
authors.initials: M
authors.lastname: Fragoso
authors.affiliation: Department of Surgery, University of Colorado, Aurora, CO, USA. anirban.banerjee@ucdenver.edu.
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado Health Sciences Center, East 17th Ave, Aurora, CO, 12801, USA. kirk.hansen@ucdenver.edu.
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Hansen
mesh_terms: D000818:Animals; D002244:Carbon / Q000378:metabolism*; D006019:Glycolysis; D007553:Isotope Labeling / Q000379:methods*; D019344:Lactic Acid / Q000097:blood; D064688:Metabolic Flux Analysis; D055432:Metabolomics / Q000379:methods*; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000097:blood / Q000378:metabolism*; D014947:Wounds and Injuries / Q000097:blood / Q000378:metabolism*
chemical_list: D019344:Lactic Acid; D002244:Carbon