{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:06:09Z","timestamp":1789139169478,"version":"build-2803163510"},"reference-count":86,"publisher":"Wiley","license":[{"start":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T00:00:00Z","timestamp":1748649600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Heterogeneity in the response to exercise training is widely demonstrated in the literature. Although the variability in exercise acclimation is not entirely understood, a large portion of exercise response variability is attributable to genetic heritability potentially due to inherited maternal mitochondrial characteristics. Humans exhibit a heterogenous genome and mitochondrial haplotype; however much of the preclinical research proposed to investigate molecular transducers of exercise has been implemented using mouse models that lack mitochondrial and nuclear genomic diversity. Leveraging a novel rat model of heterogeneous genome, OKC\u2010HET rats, we investigated the impact of mitochondrial (mt) haplotype on exercise training. We hypothesized that rats with divergent mitochondrial genomes will respond differently to endurance exercise training. OKC\u2010HET rats aged 18\u201319 months old were subjected to 8 weeks of voluntary wheel running as their endurance exercise training programme. We found mt haplotype\u2010specific effects on responses to endurance exercise and motor co\u2010ordination, which were consistent with mitochondrial bioenergetics and markers of oxidative stress. Mitochondrial copy number and the expression of mitochondrial proteins were similar between the two mt haplotypes, suggesting intrinsic alterations of mitochondrial functions by the two distinct mitochondrial genomes. Motor co\u2010ordination and fragmentation of acetylcholine receptors were also affected by mitochondrial haplotype. The mt haplotype effects on training responses were specific to biological sex also. Collectively we report that mitochondrial haplotype significantly affects responses to endurance exercise in a sex\u2010specific manner.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16765-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Mitochondrial haplotype affects the responses to endurance exercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Sex modulates the effects of mitochondrial haplotype in the responses to endurance training.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Mitochondrial DNA (mtDNA) deletion frequency increases following endurance exercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>mtDNA deletion frequency is higher in males than females after endurance exercise in OKC\u2010HET rats.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp288330","type":"journal-article","created":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T14:54:38Z","timestamp":1748703278000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mitochondrial haplotype and sex modulate responses to endurance exercise training"],"prefix":"10.1113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2743-7099","authenticated-orcid":false,"given":"Bumsoo","family":"Ahn","sequence":"first","affiliation":[{"name":"Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"},{"name":"Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6003-0592","authenticated-orcid":false,"given":"Tianhao","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Pettit\u2010Mee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9123-3472","authenticated-orcid":false,"given":"Robert V.","family":"Musci","sequence":"additional","affiliation":[{"name":"Department of Health and Human Sciences, Frank R Seaver College of Science and Engineering Loyola Marymount University  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8460-8616","authenticated-orcid":false,"given":"Jonathan","family":"Wanagat","sequence":"additional","affiliation":[{"name":"Divisions of Geriatrics, Department of Medicine University of California Los Angeles  Los Angeles California USA"},{"name":"Veterans Administration Greater Los Angeles Healthcare System  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoang Van M.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences University of Oklahoma Health Sciences  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlan","family":"Richardson","sequence":"additional","affiliation":[{"name":"Oklahoma City VA Medical Center  Oklahoma City Oklahoma USA"},{"name":"Department of Biochemistry &amp; Physiology University of Oklahoma Health Sciences  Oklahoma City Oklahoma USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,31]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.04.004"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13569"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12375"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005768-200001000-00012"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg739"},{"issue":"6","key":"e_1_2_5_7_1","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1152\/jappl.1979.47.6.1278","article-title":"Maximum oxygen\u2010consumption of rats and its changes with various experimental procedures","volume":"47","author":"Bedford T. G.","year":"1979","journal-title":"Journal of Applied Physiology"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20131433"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00309.2007"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.07.018"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2012.913"},{"issue":"3","key":"e_1_2_5_12_1","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1093\/gerona\/glz298","article-title":"Bring back the rat!","volume":"75","author":"Carter C. S.","year":"2020","journal-title":"The Journals of Gerontology\u2010Series A, Biological Sciences and Medical Sciences"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2020.06.004"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00965.2015"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.47.5.653"},{"issue":"4","key":"e_1_2_5_16_1","doi-asserted-by":"crossref","first-page":"R926","DOI":"10.1152\/ajpregu.00694.2005","article-title":"Novel quantitative phenotypes of exercise training in mouse models","volume":"290","author":"De Bono J. P.","year":"2006","journal-title":"American Journal of Physiology\u2010Regulatory, Integrative and Comparative Physiology"},{"issue":"1","key":"e_1_2_5_17_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1152\/jappl.1996.80.1.261","article-title":"Composition and size of type I, IIA, IID\/X, and IIB fibres and citrate synthase activity of rat muscle","volume":"80","author":"Delp M. D.","year":"1996","journal-title":"Journal of Applied Physiology"},{"issue":"4","key":"e_1_2_5_18_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1161\/01.ATV.8.4.402","article-title":"Heredity and changes in plasma lipids and lipoproteins after short\u2010term exercise training in men","volume":"8","author":"Despr\u00e9s J. P.","year":"1988","journal-title":"Arteriosclerosis"},{"key":"e_1_2_5_19_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/978-1-4939-7831-1_3","article-title":"High\u2010resolution FluoRespirometry and OXPHOS protocols for human cells, permeabilized fibres from small biopsies of muscle, and isolated mitochondria","volume":"1782","author":"Doerrier C.","year":"2018","journal-title":"Methods in Molecular Biology"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2018.1559556"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.08.036"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-022-00668-3"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1139\/y93-128"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/295163a0"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130029"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00259.2019"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.07.066"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00578.2005"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1089\/rej.2014.1623"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2009.03.013"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1249\/01.mss.0000241649.15006.b8"},{"key":"e_1_2_5_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11357-021-00351-z"},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glx058"},{"issue":"3","key":"e_1_2_5_34_1","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1152\/jappl.1985.59.3.826","article-title":"Effect of voluntary exercise on longevity of rats","volume":"59","author":"Holloszy J. O.","year":"1985","journal-title":"Journal of Applied Physiology (1985)"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00421-009-1177-4"},{"key":"e_1_2_5_36_1","doi-asserted-by":"crossref","first-page":"1328","DOI":"10.3389\/fphys.2019.01328","article-title":"Muscle\u2010specific sensitivity to voluntary physical activity and detraining","volume":"10","author":"Hyatt J. P. K.","year":"2019","journal-title":"Frontiers in Physiology"},{"key":"e_1_2_5_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/35047064"},{"key":"e_1_2_5_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00643744"},{"key":"e_1_2_5_39_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjsm.2004.014068"},{"key":"e_1_2_5_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0300-9629(90)90694-N"},{"issue":"1","key":"e_1_2_5_41_1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s00421-004-1061-1","article-title":"Effects of prolonged voluntary wheel\u2010running on muscle structure and function in rat skeletal muscle","volume":"92","author":"Kariya F.","year":"2004","journal-title":"European Journal of Applied Physiology"},{"key":"e_1_2_5_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14323"},{"key":"e_1_2_5_43_1","doi-asserted-by":"publisher","DOI":"10.5213\/inj.2142170.085"},{"key":"e_1_2_5_44_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.14139"},{"key":"e_1_2_5_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12880"},{"key":"e_1_2_5_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glz267"},{"key":"e_1_2_5_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.61"},{"key":"e_1_2_5_48_1","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00822.2015"},{"key":"e_1_2_5_49_1","first-page":"114","article-title":"Lost in translation: animal models and clinical trials in cancer treatment","volume":"6","author":"Mak I. W. Y.","year":"2014","journal-title":"American Journal of Translational Research"},{"key":"e_1_2_5_50_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-0925"},{"issue":"1","key":"e_1_2_5_51_1","first-page":"4","article-title":"Comparative analysis of mouse skeletal muscle fibre type composition and contractile responses to calcium channel blocker","volume":"5","author":"M\u00e4ntt\u00e4ri S.","year":"2005","journal-title":"BioMed Central Physiology [Electronic Resource]"},{"issue":"8","key":"e_1_2_5_52_1","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1046\/j.1432-1033.2002.02867.x","article-title":"Mitochondrial DNA deletion mutations: A causal role in sarcopenia","volume":"269","author":"Mckenzie D.","year":"2002","journal-title":"European Journal of Biochemistry"},{"key":"e_1_2_5_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02102807"},{"key":"e_1_2_5_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.02.074"},{"key":"e_1_2_5_55_1","first-page":"217","article-title":"Exotic mice as models for aging research: Polemic and prospectus","volume":"20","author":"Miller R. A.","year":"1999","journal-title":"Neurobiology of Aging"},{"key":"e_1_2_5_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.10.005"},{"key":"e_1_2_5_57_1","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41586-023-06877-w","article-title":"Temporal dynamics of the multi\u2010omic response to endurance exercise training","volume":"629","author":"MoTr P.","year":"2024","journal-title":"Nature"},{"issue":"10","key":"e_1_2_5_58_1","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1016\/S0531-5565(01)00145-0","article-title":"Voluntary and forced exercise influence the survival and body composition of ageing male rats differently","volume":"36","author":"Narath E.","year":"2001","journal-title":"Experimental Gerontology"},{"key":"e_1_2_5_59_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2002-220519"},{"key":"e_1_2_5_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smhs.2019.08.008"},{"key":"e_1_2_5_61_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP280389"},{"key":"e_1_2_5_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.04.013"},{"key":"e_1_2_5_63_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2010.00628.x"},{"key":"e_1_2_5_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jshs.2024.05.001"},{"issue":"5","key":"e_1_2_5_65_1","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1249\/00005768-198410000-00012","article-title":"Sensitivity of maximal aerobic power to training is genotype\u2010dependent","volume":"16","author":"PrudHomme D.","year":"1984","journal-title":"Medicine & Science in Sports & Exercise"},{"key":"e_1_2_5_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.23"},{"key":"e_1_2_5_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.05.018"},{"issue":"2","key":"e_1_2_5_68_1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/genetics\/48.2.205","article-title":"Selection for radiation resistance in mice","volume":"48","author":"Roderick T. H.","year":"1963","journal-title":"Genetics"},{"key":"e_1_2_5_69_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2840-6-38"},{"key":"e_1_2_5_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23896"},{"key":"e_1_2_5_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4598(199902)22:2<258::AID-MUS15>3.0.CO;2-1"},{"key":"e_1_2_5_72_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00069.2021"},{"key":"e_1_2_5_73_1","doi-asserted-by":"publisher","DOI":"10.1249\/MSS.0000000000002859"},{"key":"e_1_2_5_74_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glad056"},{"key":"e_1_2_5_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.physbeh.2011.11.011"},{"issue":"18","key":"e_1_2_5_76_1","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2200549119","article-title":"Mitochondrial mutations alter endurance exercise response and determinants in mice","volume":"119","author":"Schaefer P. M.","year":"2022","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"e_1_2_5_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/0531-5565(95)02032-2"},{"key":"e_1_2_5_78_1","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt90"},{"issue":"03","key":"e_1_2_5_79_1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1055\/s-2008-1025756","article-title":"Inheritance of human skeletal muscle and anaerobic capacity adaptation to high\u2010intensity intermittent training","volume":"07","author":"Simoneau J. A.","year":"1986","journal-title":"International Journal of Sports Medicine"},{"key":"e_1_2_5_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12427"},{"key":"e_1_2_5_81_1","doi-asserted-by":"publisher","DOI":"10.1177\/0300985815610391"},{"key":"e_1_2_5_82_1","doi-asserted-by":"publisher","DOI":"10.1177\/002215540004800506"},{"issue":"11","key":"e_1_2_5_83_1","doi-asserted-by":"crossref","first-page":"B492","DOI":"10.1093\/gerona\/54.11.B492","article-title":"Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program","volume":"54","author":"Turturro A.","year":"1999","journal-title":"Journals of Gerontology\u2010 Series A, Biological Sciences and Medical Sciences"},{"key":"e_1_2_5_84_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002220107"},{"key":"e_1_2_5_85_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13842"},{"key":"e_1_2_5_86_1","doi-asserted-by":"publisher","DOI":"10.5213\/inj.1938038.019"},{"key":"e_1_2_5_87_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.078865.108"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP288330","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,31]],"date-time":"2025-05-31T14:54:42Z","timestamp":1748703282000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP288330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,31]]},"references-count":86,"alternative-id":["10.1113\/JP288330"],"URL":"https:\/\/doi.org\/10.1113\/jp288330","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,31]]},"assertion":[{"value":"2024-12-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"JP288330"}}