{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T15:03:54Z","timestamp":1780499034160,"version":"3.54.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Traumatic brain injury (TBI) often leads to lasting impairments in physical performance, yet its impact on aerobic function and the potential for recovery through exercise remain poorly understood. In this study, we used a well-established controlled cortical impact (CCI) model in mice to address three gaps in the preclinical TBI literature: the effect of injury on voluntary activity and energy metabolism, the extent to which exercise tolerance and cardiorespiratory fitness can be restored through moderate-intensity aerobic training, and whether these responses differ between sexes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Voluntary wheel running and metabolic outputs following CCI were quantified via the Comprehensive Lab Animal Monitoring System (CLAMS), while maximal oxygen uptake (VO\n                      <jats:sub>2<\/jats:sub>\n                      max) and time to exhaustion were measured before and after a 10-day treadmill training regimen initiated during the subacute phase.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Both sexes displayed similar acute reductions in VO\n                      <jats:sub>2<\/jats:sub>\n                      max following TBI; however, only females exhibited significant gains in VO\n                      <jats:sub>2<\/jats:sub>\n                      max and exercise tolerance after exercise training, alongside higher spontaneous activity, greater energy expenditure, and smaller lesion volumes compared to males. Exercised females also exhibited selective cardiac upregulation of mitochondrial complex activity, indicating that enhanced mitochondrial capacity paralleled improved aerobic performance. In contrast, injured males showed persistent deficits and no measurable improvement in cardiovascular fitness or mitochondrial physiology from training, indicating a sex-specific limitation in aerobic adaptation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings reveal a divergence in post-TBI exercise responsiveness and highlight the need for sex-specific, physiology-guided rehabilitation strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2025.1700462","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T06:22:29Z","timestamp":1761805349000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Aerobic training improves exercise capacity after traumatic brain injury in female, but not male, mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Kate","family":"Karelina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Corbin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claymore T.","family":"Gumbo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Payne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Reger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayden","family":"Barr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikayla","family":"Oldham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Shoemaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakthijothi","family":"Muthu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ethan","family":"Meadows","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Hollander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary M.","family":"Weil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1097\/HTR.0000000000000639","article-title":"Physical activity interventions for individuals with a mild traumatic brain injury:: a scoping review","volume":"36","author":"Alarie","year":"2021","journal-title":"J. Head. Trauma Rehabil."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1113\/EP088548","article-title":"Physiological sex differences affect the integrative response to exercise: acute and chronic implications","volume":"105","author":"Ansdell","year":"2020","journal-title":"Exp. Physiol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1089\/neu.2023.0168","article-title":"Exercise intolerance after mild traumatic brain injury occurs in all subtypes in the adult population","volume":"41","author":"Antonellis","year":"2024","journal-title":"J. Neurotrauma"},{"key":"B4","doi-asserted-by":"publisher","first-page":"e1972","DOI":"10.1002\/pri.1972","article-title":"Effects of continuous aerobic training associated with resistance training on maximal and submaximal exercise tolerance, fatigue, and quality of life of patients post-COVID-19","volume":"28","author":"Araujo","year":"2023","journal-title":"Physiother. Res. Int."},{"key":"B5","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.psc.2013.12.001","article-title":"Emotional and behavioral dyscontrol after traumatic brain injury","volume":"37","author":"Arciniegas","year":"2014","journal-title":"Psychiatr. Clin. North Am."},{"key":"B6","doi-asserted-by":"publisher","first-page":"15951","DOI":"10.3390\/ijms242115951","article-title":"Mitochondrial complex I and beta-amyloid peptide interplay in Alzheimer's disease: a critical review of new and old little regarded findings","volume":"24","author":"Atlante","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.exger.2016.04.011","article-title":"Sex-related differences in the wheel-running activity of mice decline with increasing age","volume":"87","author":"Bartling","year":"2017","journal-title":"Exp. Gerontol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.2174\/1573403X15666190321141856","article-title":"Gender differences in hemodynamic regulation and cardiovascular adaptations to dynamic exercise","volume":"16","author":"Bassareo","year":"2020","journal-title":"Curr. Cardiol. Rev."},{"key":"B9","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1097\/JSM.0000000000000809","article-title":"Practical management: prescribing subsymptom threshold aerobic exercise for sport-related concussion in the outpatient setting","volume":"31","author":"Bezherano","year":"2021","journal-title":"Clin. J. Sport Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"S446","DOI":"10.1097\/00005768-200106001-00013","article-title":"Individual differences in response to regular physical activity","volume":"33","author":"Bouchard","year":"2001","journal-title":"Med. Sci. Sports Exerc"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1089\/neu.2014.3352","article-title":"Long-term consequences of traumatic brain injury: current status of potential mechanisms of injury and neurological outcomes","volume":"32","author":"Bramlett","year":"2015","journal-title":"J. Neurotrauma"},{"key":"B12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/s00421-021-04802-5","article-title":"Analysis of sex-based differences in energy substrate utilization during moderate-intensity aerobic exercise","volume":"122","author":"Cano","year":"2022","journal-title":"Eur. J. Appl. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1159\/000099208","article-title":"Skeletal muscle of female rats exhibit higher mitochondrial mass and oxidative-phosphorylative capacities compared to males","volume":"19","author":"Colom","year":"2007","journal-title":"Cell Physiol. Biochem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/j.lfs.2013.07.005","article-title":"Evaluation of the cardiolipin biosynthetic pathway and its interactions in the diabetic heart","volume":"93","author":"Croston","year":"2013","journal-title":"Life Sci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"54052","DOI":"10.3791\/54052","article-title":"The treadmill fatigue test: a simple, high-throughput assay of fatigue-like behavior for the mouse","author":"Dougherty","year":"2016","journal-title":"J. Vis. Exp."},{"key":"B16","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1123\/jsep.27.3.350","article-title":"Some like it vigorous: measuring individual differences in the preference for and tolerance of exercise intensity","volume":"27","author":"Ekkekakis","year":"2005","journal-title":"J. Sport Exerc. Psy"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.3390\/life12091400","article-title":"Alterations in baroreflex sensitivity and blood pressure variability following sport-related concussion","volume":"12","author":"Ellingson","year":"2022","journal-title":"Life (Basel)"},{"key":"B18","doi-asserted-by":"publisher","first-page":"100","DOI":"10.3390\/brainsci7080100","article-title":"Autonomic dysfunction after mild traumatic brain injury","volume":"7","author":"Esterov","year":"2017","journal-title":"Brain Sci."},{"key":"B19","first-page":"133","article-title":"Effect of aerobic exercise training on pulmonary function and tolerance of activity in asthmatic patients","volume":"4","author":"Farid","year":"2005","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s42004-019-0172-x","article-title":"Crystal structure of the mitochondrial protein mitoNEET bound to a benze-sulfonide ligand","volume":"2","author":"Geldenhuys","year":"2019","journal-title":"Commun. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"E1325","DOI":"10.1152\/ajpendo.2000.279.6.E1325","article-title":"Determinants of the variability in respiratory exchange ratio at rest and during exercise in trained athletes","volume":"279","author":"Goedecke","year":"2000","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"B22","doi-asserted-by":"publisher","first-page":"S64","DOI":"10.1016\/j.pmrj.2011.02.008","article-title":"Exercise after traumatic brain injury: is it a double-edged sword?","volume":"3","author":"Griesbach","year":"2011","journal-title":"PM R."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1426","DOI":"10.1089\/neu.2011.2229","article-title":"Differential effects of voluntary and forced exercise on stress responses after traumatic brain injury","volume":"29","author":"Griesbach","year":"2012","journal-title":"J. Neurotrauma"},{"key":"B24","doi-asserted-by":"publisher","first-page":"3063","DOI":"10.1089\/neu.2018.6171","article-title":"Sex differences in traumatic brain injury: what we know and what we should know","volume":"36","author":"Gupte","year":"2019","journal-title":"J. Neurotraum"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1007\/s40279-019-01122-9","article-title":"Physical activity intolerance and cardiorespiratory dysfunction in patients with moderate-to-severe traumatic brain injury","volume":"49","author":"Hamel","year":"2019","journal-title":"Sports Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"E978","DOI":"10.1093\/milmed\/usab472","article-title":"Literature review of sex differences in mTBI","volume":"188","author":"Haynes","year":"2023","journal-title":"Mil. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1113\/EP091594","article-title":"Cardiac output limits maximal oxygen consumption, but what limits maximal cardiac output?","volume":"110","author":"Heinonen","year":"2025","journal-title":"Exp. Physiol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1007\/s11010-016-2748-4","article-title":"Sex differences in the regulation of spatially distinct cardiac mitochondrial subpopulations","volume":"419","author":"Hertel Ribeiro","year":"2016","journal-title":"Mol. Cell Biochem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1552531","DOI":"10.3389\/fpsyg.2025.1552531","article-title":"Exercise prescriptions for young people's emotional wellbeing: a systematic review of physical activity intensity, duration, and modality","volume":"16","author":"Huang","year":"2025","journal-title":"Front. Psychol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1249\/MSS.0000000000003300","article-title":"The biological basis of sex differences in athletic performance: consensus statement for the American college of sports medicine","volume":"55","author":"Hunter","year":"2023","journal-title":"Med. Sci. Sports Exerc"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-4365992\/v1","article-title":"The influence of sex on activity in voluntary wheel running, forced treadmill running, and open field testing","author":"Janowski","year":"2024","journal-title":"Res. Sq."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3402","DOI":"10.1093\/brain\/awl149","article-title":"Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy","volume":"129","author":"Jeppesen","year":"2006","journal-title":"Brain"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1858","DOI":"10.1089\/neu.2020.7389","article-title":"Moderate intensity treadmill exercise increases survival of newborn hippocampal neurons and improves neurobehavioral outcomes after traumatic brain injury","volume":"38","author":"Karelina","year":"2021","journal-title":"J. Neurotrauma"},{"key":"B34","doi-asserted-by":"publisher","first-page":"108684","DOI":"10.1016\/j.heares.2022.108684","article-title":"Sex differences in body composition, voluntary wheel running activity, balance performance, and auditory function in CBA\/CaJ mice across the lifespan","volume":"428","author":"Kim","year":"2023","journal-title":"Hear Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3753","DOI":"10.1113\/JP273609","article-title":"Mitochondrial energetics and calcium coupling in the heart","volume":"595","author":"Kohlhaas","year":"2017","journal-title":"J. Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.brainres.2016.01.016","article-title":"The interplay between neuropathology and activity based rehabilitation after traumatic brain injury","volume":"1640","author":"Kreber","year":"2016","journal-title":"Brain Res."},{"key":"B37","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1001\/jamapediatrics.2018.4397","article-title":"Early subthreshold aerobic exercise for sport-related concussion: a randomized clinical trial","volume":"173","author":"Leddy","year":"2019","journal-title":"JAMA Pediatr."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1406","DOI":"10.1016\/j.bbabio.2006.05.007","article-title":"Mitochondrial complex I: structural and functional aspects","volume":"1757","author":"Lenaz","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"B39","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1101\/sqb.2011.76.011965","article-title":"Transcriptional control of cardiac fuel metabolism and mitochondrial function","volume":"76","author":"Leone","year":"2011","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s12883-020-1622-x","article-title":"Improving symptom burden in adults with persistent post-concussive symptoms: a randomized aerobic exercise trial protocol","volume":"20","author":"Mercier","year":"2020","journal-title":"BMC Neurol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3377","DOI":"10.1113\/JP273480","article-title":"Refuting the myth of non-response to exercise training: 'non-responders' do respond to higher dose of training","volume":"595","author":"Montero","year":"2017","journal-title":"J. Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.apmr.2006.12.006","article-title":"Aerobic capacity after traumatic brain injury: comparison with a nondisabled cohort","volume":"88","author":"Mossberg","year":"2007","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"B43","doi-asserted-by":"publisher","first-page":"101674","DOI":"10.1016\/j.redox.2020.101674","article-title":"Mitochondrial electron transport chain: oxidative phosphorylation, oxidant production, and methods of measurement","volume":"37","author":"Nolfi-Donegan","year":"2020","journal-title":"Redox Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"135","DOI":"10.3389\/fcvm.2018.00135","article-title":"Cardiovascular effects and benefits of exercise","volume":"5","author":"Nystoriak","year":"2018","journal-title":"Front. Cardiovasc Med."},{"key":"B45","doi-asserted-by":"publisher","first-page":"e0148010","DOI":"10.1371\/journal.pone.0148010","article-title":"Graded maximal exercise testing to assess mouse cardio-metabolic phenotypes","volume":"11","author":"Petrosino","year":"2016","journal-title":"PLoS One"},{"key":"B46","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.nbd.2012.12.017","article-title":"Late exercise reduces neuroinflammation and cognitive dysfunction after traumatic brain injury","volume":"54","author":"Piao","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"B47","doi-asserted-by":"publisher","first-page":"545","DOI":"10.2522\/ptj.20060085","article-title":"Effect of aerobic training on walking capacity and maximal exercise tolerance in patients with multiple sclerosis: a randomized crossover controlled study","volume":"87","author":"Rampello","year":"2007","journal-title":"Phys. Ther."},{"key":"B48","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1002\/jnr.23896","article-title":"Sex-dependent differences in voluntary physical activity","volume":"95","author":"Rosenfeld","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"S323","DOI":"10.1016\/j.cjca.2023.08.007","article-title":"Understanding exercise capacity: from elite athlete to HFpEF","volume":"39","author":"Rowe","year":"2023","journal-title":"Can. J. Cardiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1179069519844020","DOI":"10.1177\/1179069519844020","article-title":"Sex differences in animal models of traumatic brain injury","volume":"13","author":"Rubin","year":"2019","journal-title":"J. Exp. Neurosci."},{"key":"B51","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s00421-008-0971-8","article-title":"Physical exercise increases mitochondrial function and reduces oxidative damage in skeletal muscle","volume":"105","author":"Silva","year":"2009","journal-title":"Eur. J. Appl. Physiol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1307507","DOI":"10.3389\/fnhum.2023.1307507","article-title":"Brain changes: aerobic exercise for traumatic brain injury rehabilitation","volume":"17","author":"Snowden","year":"2023","journal-title":"Front. Hum. Neurosci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/s13054-016-1318-1","article-title":"Chronic impact of traumatic brain injury on outcome and quality of life: a narrative review","volume":"20","author":"Stocchetti","year":"2016","journal-title":"Crit. Care"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1665","DOI":"10.1212\/WNL.0000000000000944","article-title":"Cerebrovascular regulation, exercise, and mild traumatic brain injury","volume":"83","author":"Tan","year":"2014","journal-title":"Neurology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1152\/japplphysiol.01295.2009","article-title":"Using molecular classification to predict gains in maximal aerobic capacity following endurance exercise training in humans","volume":"108","author":"Timmons","year":"2010","journal-title":"J. Appl. Physiol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1042\/CS20160485","article-title":"Mitochondria: a central target for sex differences in pathologies","volume":"131","author":"Ventura-Clapier","year":"2017","journal-title":"Clin. Sci. (Lond)"},{"key":"B57","doi-asserted-by":"publisher","first-page":"1286","DOI":"10.1089\/neu.2022.0363","article-title":"Putting the mind to rest: a historical foundation for rest as a treatment for traumatic brain injury","volume":"40","author":"Weil","year":"2023","journal-title":"J. Neurotrauma"},{"key":"B58","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1002\/pmrj.13091","article-title":"Exercise as a behavioral approach to improve mood in persons with traumatic brain injury","volume":"16","author":"Wender","year":"2024","journal-title":"PM R."},{"key":"B59","doi-asserted-by":"publisher","first-page":"114483","DOI":"10.1016\/j.expneurol.2023.114483","article-title":"Exercise intensity and sex alter neurometabolic, transcriptional, and functional recovery following traumatic brain injury","volume":"368","author":"White","year":"2023","journal-title":"Exp. Neurol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.freeradbiomed.2021.11.002","article-title":"Exercise improves vascular health: role of mitochondria","volume":"177","author":"Zhang","year":"2021","journal-title":"Free Radic. Biol. Med."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2025.1700462\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T06:22:30Z","timestamp":1761805350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2025.1700462\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,30]]},"references-count":60,"alternative-id":["10.3389\/fphys.2025.1700462"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2025.1700462","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,30]]},"article-number":"1700462"}}