{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T04:53:20Z","timestamp":1789275200475,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2141291"],"award-info":[{"award-number":["2141291"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Institute for Critical Technology and Applied Science (ICTAS) at Virginia Tech","award":["2141291"],"award-info":[{"award-number":["2141291"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Traumatic brain injury (TBI) is a major neurological condition affecting millions of individuals each year. Mild TBI (mTBI) manifests differently, with some individuals experiencing persistent, debilitating symptoms while others recover more rapidly. Despite its classification as \u201cmild,\u201d mTBI leads to both short- and long-term neurological effects, many of which occur due to functional changes in the brain. TBI-induced environmental changes within the brain play a critical role in shaping these functional outcomes. The importance of astrocytes in maintaining central nervous system (CNS) homeostasis has been increasingly recognized for their pivotal role in the brain\u2019s response to TBI. Previous studies showed significant TBI-associated metabolic dysregulations. Therefore, we sought to analyze how astrocytes might adapt to persistent metabolic stressors in the post-injury microenvironment and identify injury-induced shifts occurring in vivo that may contribute to chronic metabolic dysfunction. We used an astrocyte-specific genome-scale metabolic model that allowed for the input of biologically relevant uptake rates corresponding to healthy astrocytes to analyze how the activity of metabolic pathways differed in hypoxic and acidic conditions. Additionally, these fluxes were integrated with mass spectrometry-based proteomics from male Sprague-Dawley rats subjected to mTBI to identify chronic adaptive neural responses post-injury. Comparison of modeled metabolic fluxes and experimental proteomic data demonstrated remarkable alignment, with both predicting significant changes in key metabolic processes including glycolysis, oxidative phosphorylation, the TCA cycle, and the Pentose Phosphate Pathway. These overlapping signatures may represent core survival strategies, offering insight into metabolic priorities and potentially serving as biomarkers of injury adaptation or recovery capacity.<\/jats:p>","DOI":"10.3390\/ijms26136456","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T08:58:23Z","timestamp":1751878703000},"page":"6456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Integrative Constraint-Based Modeling and Proteomics Uncover Astrocytic Metabolic Adaptations to the Post-TBI Microenvironment"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5419-5454","authenticated-orcid":false,"given":"Kelsey A.","family":"Wilson","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering & Mechanics, Virginia Tech, 325 Stanger St., Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8247-305X","authenticated-orcid":false,"given":"Caiti-Erin","family":"Talty","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering & Mechanics, Virginia Tech, 325 Stanger St., Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1041-1481","authenticated-orcid":false,"given":"Brian C.","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering & Mechanics, Virginia Tech, 325 Stanger St., Blacksburg, VA 24061, USA"},{"name":"School of Biomedical Engineering and Sciences, Virginia Tech, 325 Stanger St., Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3422-2704","authenticated-orcid":false,"given":"Pamela J.","family":"VandeVord","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering & Mechanics, Virginia Tech, 325 Stanger St., Blacksburg, VA 24061, USA"},{"name":"Veterans Affairs Medical Center, 1970 Roanoke Blvd, Salem, VA 24153, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3310\/nihropenres.13377.1","article-title":"An international, prospective observational study on traumatic brain injury epidemiology study protocol: GEO-TBI: Incidence","volume":"3","author":"Joannides","year":"2023","journal-title":"NIHR Open Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e075049","DOI":"10.1136\/bmjopen-2023-075049","article-title":"Global, regional and national burden of traumatic brain injury and spinal cord injury, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019","volume":"13","author":"Guan","year":"2023","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss6609a1","article-title":"Traumatic brain injury\u2013related emergency department visits, hospitalizations, and deaths\u2014United States, 2007 and 2013","volume":"66","author":"Taylor","year":"2017","journal-title":"MMWR. Surveill. Summ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1089\/neu.2017.5317","article-title":"Modeling the Long-Term Consequences of Repeated Blast-Induced Mild Traumatic Brain Injuries","volume":"34","author":"Agoston","year":"2017","journal-title":"J. Neurotrauma"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.1016\/j.jalz.2014.04.012","article-title":"Military traumatic brain injury: A review","volume":"10","author":"Chapman","year":"2014","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1016\/j.brat.2005.03.010","article-title":"Social anxiety and posttraumatic stress in combat veterans: Relations to well-being and character strengths","volume":"44","author":"Kashdan","year":"2006","journal-title":"Behav. Res. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1097\/00005373-198812000-00004","article-title":"The epidemiology of mild, uncomplicated brain injury","volume":"28","author":"Kraus","year":"1988","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1212\/01.WNL.0000068008.78394.2C","article-title":"Head trauma preceding PD: A case-control study","volume":"60","author":"Bower","year":"2003","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"597","DOI":"10.3171\/jns.2005.103.4.0597","article-title":"Cerebral acid-base homeostasis after severe traumatic brain injury","volume":"103","author":"Clausen","year":"2005","journal-title":"J. Neurosurg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/jcbfm.2012.186","article-title":"Extracellular brain pH with or without hypoxia is a marker of profound metabolic derangement and increased mortality after traumatic brain injury","volume":"33","author":"Timofeev","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1001\/jamaneurol.2016.0091","article-title":"Pathophysiologic Mechanisms of Cerebral Ischemia and Diffusion Hypoxia in Traumatic Brain Injury","volume":"73","author":"Veenith","year":"2016","journal-title":"JAMA Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/jcbfm.1985.33","article-title":"Lactic acidosis and recovery of mitochondrial function following forebrain ischemia in the rat","volume":"5","author":"Hillered","year":"1985","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/S0196-0644(85)80055-X","article-title":"Brain acidosis","volume":"14","author":"Rehncrona","year":"1985","journal-title":"Ann. Emerg. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/jcbfm.1981.35","article-title":"Brain lactic acidosis and ischemic cell damage: 2. Histopathology","volume":"1","author":"Kalimo","year":"1981","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1046\/j.1471-4159.1999.0731549.x","article-title":"Acidosis potentiates oxidative neuronal death by multiple mechanisms","volume":"73","author":"Ying","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1097\/01.ta.0000196644.64653.d8","article-title":"Prehospital hypoxia affects outcome in patients with traumatic brain injury: A prospective multicenter study","volume":"61","author":"Chi","year":"2006","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1089\/neu.2013.3087","article-title":"Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury","volume":"31","author":"Yan","year":"2014","journal-title":"J. Neurotrauma"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1089\/neu.2005.22.955","article-title":"Monitoring of cerebral blood flow and metabolism in traumatic brain injury","volume":"22","author":"Soustiel","year":"2005","journal-title":"J. Neurotrauma"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3171\/jns.1992.77.3.0360","article-title":"Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography","volume":"77","author":"Bouma","year":"1992","journal-title":"J. Neurosurg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1097\/01.CCM.0000127777.16609.08","article-title":"Diffusion limited oxygen delivery following head injury","volume":"32","author":"Menon","year":"2004","journal-title":"Crit. Care Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00401-009-0619-8","article-title":"Astrocytes: Biology and pathology","volume":"119","author":"Sofroniew","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1002\/glia.23250","article-title":"Astrocyte glycogen and lactate: New insights into learning and memory mechanisms","volume":"66","author":"Alberini","year":"2018","journal-title":"Glia"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1217451","DOI":"10.3389\/fnins.2023.1217451","article-title":"Astrocyte metabolism and signaling pathways in the CNS","volume":"17","author":"Zhang","year":"2023","journal-title":"Front. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Takahashi, S. (2021). Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126568"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Guilhaume-Correa, F., Pickrell, A.M., and VandeVord, P.J. (2023). The Imbalance of Astrocytic Mitochondrial Dynamics Following Blast-Induced Traumatic Brain Injury. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020329"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"614410","DOI":"10.3389\/fnagi.2020.614410","article-title":"Mitochondrial Dynamics and Bioenergetic Alteration During Inflammatory Activation of Astrocytes","volume":"12","author":"Rahman","year":"2020","journal-title":"Front. Aging Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1111\/acel.12268","article-title":"Astrocytic metabolic and inflammatory changes as a function of age","volume":"13","author":"Jiang","year":"2014","journal-title":"Aging Cell"},{"key":"ref_28","first-page":"23","article-title":"Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network","volume":"9","author":"Barreto","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1471-4159.2009.06003.x","article-title":"The in vivo neuron-to-astrocyte lactate shuttle in human brain: Evidence from modeling of measured lactate levels during visual stimulation","volume":"109","author":"Mangia","year":"2009","journal-title":"J. Neurochem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Sharma, B., Schmidt, L., Nguyen, C., Kiernan, S., Dexter-Meldrum, J., Kuschner, Z., Ellis, S., Bhatia, N.D., Agriantonis, G., and Whittington, J. (2024). The effect of L-carnitine on critical illnesses such as traumatic brain injury (TBI), acute kidney injury (AKI), and hyperammonemia (HA). Metabolites, 14.","DOI":"10.3390\/metabo14070363"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"109370","DOI":"10.1016\/j.neuropharm.2022.109370","article-title":"The mammalian purine salvage pathway as an exploitable route for cerebral bioenergetic support after brain injury","volume":"224","author":"Gessner","year":"2023","journal-title":"Neuropharmacology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1089\/neu.2012.2391","article-title":"Detection of Structural and Metabolic Changes in Traumatically Injured Hippocampus by Quantitative Differential Proteomics","volume":"30","author":"Wu","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1021\/acs.jproteome.3c00544","article-title":"Multiplexed Quantitative Proteomics Reveals Proteomic Alterations in Two Rodent Traumatic Brain Injury Models","volume":"23","author":"Park","year":"2024","journal-title":"J. Proteome Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1759091420914768","DOI":"10.1177\/1759091420914768","article-title":"Unbiased Proteomic Approach Identifies Pathobiological Profiles in the Brains of Preclinical Models of Repetitive Mild Traumatic Brain Injury, Tauopathy, and Amyloidosis","volume":"12","author":"Ojo","year":"2020","journal-title":"ASN Neuro"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0197-0186(00)00106-6","article-title":"Metabolism of [1-13C] glucose and [2-13C] acetate in the hypoxic rat brain","volume":"38","author":"Chateil","year":"2001","journal-title":"Neurochem. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1523\/JNEUROSCI.22-05-01523.2002","article-title":"Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: Elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism","volume":"22","author":"Lebon","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/(SICI)1098-1136(199909)27:3<239::AID-GLIA5>3.0.CO;2-K","article-title":"Rapid uptake and degradation of glycine by astroglial cells in culture: Synthesis and release of serine and lactate","volume":"27","author":"Verleysdonk","year":"1999","journal-title":"Glia"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1002\/jnr.490350510","article-title":"Uptake, release and metabolism of alaume in neurons and astrocytes in primary cultures","volume":"35","author":"Westergaard","year":"1993","journal-title":"J. Neurosci. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0006-8993(97)00514-3","article-title":"The entry of [1-13C] glucose into biochemical pathways reveals a complex compartmentation and metabolite trafficking between glia and neurons: A study by 13C-NMR spectroscopy","volume":"765","author":"Aureli","year":"1997","journal-title":"Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8235","DOI":"10.1073\/pnas.96.14.8235","article-title":"Determination of the rate of the glutamate\/glutamine cycle in the human brain by in vivo 13C NMR","volume":"96","author":"Shen","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/s11064-008-9840-4","article-title":"Glial metabolism of isoleucine","volume":"34","author":"Murin","year":"2009","journal-title":"Neurochem. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3389\/fendo.2013.00156","article-title":"Metabolic Flux and Compartmentation Analysis in the Brain In vivo","volume":"4","author":"Lanz","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/(SICI)1099-1492(199911)12:7<451::AID-NBM571>3.0.CO;2-E","article-title":"Quantitative 13C NMR studies of metabolic compartmentation in the adult mammalian brain","volume":"12","author":"Cruz","year":"1999","journal-title":"NMR Biomed."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fnene.2011.00005","article-title":"A comprehensive metabolic profile of cultured astrocytes using isotopic transient metabolic flux analysis and 13C-labeled glucose","volume":"3","author":"Amaral","year":"2011","journal-title":"Front. Neuroenergetics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0006-8993(01)02342-3","article-title":"The uptake of cysteine in cultured primary astrocytes and neurons","volume":"902","author":"Shanker","year":"2001","journal-title":"Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/BF00965045","article-title":"Uptake of leucine, lysine, aspartic acid, and glycine into isolated neurons and astrocytes","volume":"6","author":"Hannuniemi","year":"1981","journal-title":"Neurochem. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1002\/1098-1136(200012)32:3<286::AID-GLIA80>3.0.CO;2-P","article-title":"NMR spectroscopic study on the metabolic fate of [3-13C] alanine in astrocytes, neurons, and cocultures: Implications for glia-neuron interactions in neurotransmitter metabolism","volume":"32","author":"Zwingmann","year":"2000","journal-title":"Glia"},{"key":"ref_48","first-page":"370","article-title":"Regulation of glial metabolism studied by 13C-NMR","volume":"16","author":"Zwingmann","year":"2003","journal-title":"NMR Biomed. Int. J. Devoted Dev. Appl. Magn. Reson. In Vivo"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"E100","DOI":"10.1152\/ajpendo.2001.281.1.E100","article-title":"A mathematical model of compartmentalized neurotransmitter metabolism in the human brain","volume":"281","author":"Gruetter","year":"2001","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.neuroscience.2024.09.039","article-title":"Mild traumatic brain injury gives rise to chronic depression-like behavior and associated alterations in glutamatergic protein expression","volume":"560","author":"Talty","year":"2024","journal-title":"Neuroscience"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"15971","DOI":"10.1523\/JNEUROSCI.1702-15.2015","article-title":"NMDA receptors containing the GluN2D subunit control neuronal function in the subthalamic nucleus","volume":"35","author":"Swanger","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Browning, J.L., Wilson, K.A., Shandra, O., Wei, X., Mahmutovic, D., Maharathi, B., Robel, S., VandeVord, P.J., and Olsen, M.L. (2024). Applying Proteomics and Computational Approaches to Identify Novel Targets in Blast-Associated Post-Traumatic Epilepsy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052880"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6456\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:04:32Z","timestamp":1760033072000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/13\/6456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":52,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["ijms26136456"],"URL":"https:\/\/doi.org\/10.3390\/ijms26136456","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]}}}