{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:26:05Z","timestamp":1791847565830,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T00:00:00Z","timestamp":1699488000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000856","name":"The Colt Foundation","doi-asserted-by":"publisher","award":["277189"],"award-info":[{"award-number":["277189"]}],"id":[{"id":"10.13039\/501100000856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000856","name":"The Colt Foundation","doi-asserted-by":"publisher","award":["19\/20.007"],"award-info":[{"award-number":["19\/20.007"]}],"id":[{"id":"10.13039\/501100000856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000856","name":"The Colt Foundation","doi-asserted-by":"publisher","award":["WKR0-2021-0003"],"award-info":[{"award-number":["WKR0-2021-0003"]}],"id":[{"id":"10.13039\/501100000856","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Defence Medical Services Research Steering Group","award":["277189"],"award-info":[{"award-number":["277189"]}]},{"name":"Defence Medical Services Research Steering Group","award":["19\/20.007"],"award-info":[{"award-number":["19\/20.007"]}]},{"name":"Defence Medical Services Research Steering Group","award":["WKR0-2021-0003"],"award-info":[{"award-number":["WKR0-2021-0003"]}]},{"name":"British Journal of Anaesthesia\/Royal College of Anaesthetists","award":["277189"],"award-info":[{"award-number":["277189"]}]},{"name":"British Journal of Anaesthesia\/Royal College of Anaesthetists","award":["19\/20.007"],"award-info":[{"award-number":["19\/20.007"]}]},{"name":"British Journal of Anaesthesia\/Royal College of Anaesthetists","award":["WKR0-2021-0003"],"award-info":[{"award-number":["WKR0-2021-0003"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel\u2013characterised by the inability to thermoregulate during exercise. The ability to thermoregulate can be studied using a standardised heat tolerance test (HTT) developed by The Institute of Naval Medicine. In this study, we investigated whole blood gene expression (at baseline, 2 h post-HTT and 24 h post-HTT) in male subjects with either a history of EHI or known susceptibility to malignant hyperthermia (MHS): a pharmacogenetic condition with similar clinical phenotype. Compared to healthy controls at baseline, 291 genes were differentially expressed in the EHI cohort, with functional enrichment in inflammatory response genes (up to a four-fold increase). In contrast, the MHS cohort featured 1019 differentially expressed genes with significant down-regulation of genes associated with oxidative phosphorylation (OXPHOS). A number of differentially expressed genes in the inflammation and OXPHOS pathways overlapped between the EHI and MHS subjects, indicating a common underlying pathophysiology. Transcriptome profiles between subjects who passed and failed the HTT (based on whether they achieved a plateau in core temperature or not, respectively) were not discernable at baseline, and HTT was shown to elevate inflammatory response gene expression across all clinical phenotypes.<\/jats:p>","DOI":"10.3390\/ijms242216124","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T08:08:58Z","timestamp":1699517338000},"page":"16124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Comparison of Transcriptomic Changes in Survivors of Exertional Heat Illness with Malignant Hyperthermia Susceptible Patients"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5223-7616","authenticated-orcid":false,"given":"Leon","family":"Chang","sequence":"first","affiliation":[{"name":"Leeds Institute of Medical Research at St James\u2019s, University of Leeds, Leeds LS9 7TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9397-401X","authenticated-orcid":false,"given":"Lois","family":"Gardner","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research at St James\u2019s, University of Leeds, Leeds LS9 7TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"House","sequence":"additional","affiliation":[{"name":"Survival and Thermal Medicine Department, Institute of Naval Medicine, Alverstoke, Hampshire PO12 2DL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Daly","sequence":"additional","affiliation":[{"name":"Malignant Hyperthermia Unit, St James\u2019s University Hospital, Leeds LS9 7TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrian","family":"Allsopp","sequence":"additional","affiliation":[{"name":"Survival and Thermal Medicine Department, Institute of Naval Medicine, Alverstoke, Hampshire PO12 2DL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Roiz de Sa","sequence":"additional","affiliation":[{"name":"Survival and Thermal Medicine Department, Institute of Naval Medicine, Alverstoke, Hampshire PO12 2DL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Anne","family":"Shaw","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research at St James\u2019s, University of Leeds, Leeds LS9 7TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8127-1739","authenticated-orcid":false,"given":"Philip M.","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Leeds Institute of Medical Research at St James\u2019s, University of Leeds, Leeds LS9 7TF, UK"},{"name":"Malignant Hyperthermia Unit, St James\u2019s University Hospital, Leeds LS9 7TF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"American College of Sports Medicine, Armstrong, L.E., Casa, D.J., Millard-Stafford, M., Moran, D.S., Pyne, S.W., and Roberts, W.O. (2007). American college of sports medicine position stand. Exertional heat illness during training and competition. Med. Sci. Sport. Exerc., 39, 556\u2013572.","DOI":"10.1249\/MSS.0b013e31802fa199"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1161\/CIRCULATIONAHA.108.804617","article-title":"Sudden deaths in young competitive athletes: Analysis of 1866 deaths in the united states, 1980\u20132006","volume":"119","author":"Maron","year":"2009","journal-title":"Circulation."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e000055","DOI":"10.1136\/bmjsem-2015-000055","article-title":"Susceptibility to exertional heat illness and hospitalisation risk in UK military personnel","volume":"1","author":"Stacey","year":"2015","journal-title":"BMJ Open Sport Exerc. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1136\/jramc-142-02-02","article-title":"Heat Illness: A Comparison between UK and Cyprus Reports","volume":"142","author":"Bricknell","year":"1996","journal-title":"J. R. Army Med. Corps."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1016\/0140-6736(91)92304-K","article-title":"Evidence for related myopathies in exertional heat stroke and malignant hyperthermia","volume":"338","author":"Hopkins","year":"1991","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1002\/mus.1112","article-title":"Maximal exercise and muscle energy metabolism after recovery from exercise hyperthermia syndrome","volume":"24","author":"Vanuxem","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1111\/anae.15317","article-title":"Malignant hyperthermia 2020: Guideline from the association of anaesthetists","volume":"76","author":"Hopkins","year":"2021","journal-title":"Anaesthesia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1136\/jmedgenet-2019-106461","article-title":"Investigating the genetic susceptibility to exertional heat illness","volume":"57","author":"Gardner","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.jsams.2018.11.012","article-title":"Thermoregulation and markers of muscle breakdown in malignant hyperthermia susceptible volunteers during an acute heat tolerance test","volume":"22","author":"House","year":"2018","journal-title":"J. Sci. Med. Sport"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1056\/NEJMra011089","article-title":"Heat stroke","volume":"346","author":"Bouchama","year":"2002","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1883","DOI":"10.1002\/cphy.c100082","article-title":"Integrated physiological mechanisms of exercise performance, adaptation, and maladaptation to heat stress","volume":"1","author":"Sawka","year":"2011","journal-title":"Compr. Physiol."},{"key":"ref_12","first-page":"87","article-title":"Stress and immunosenescence: The role of telomerase","volume":"101","author":"Heim","year":"2018","journal-title":"Psychoneuroendocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.3389\/fimmu.2017.01078","article-title":"Chronic inflammation in immune aging: Role of pattern recognition receptor crosstalk with the telomere complex?","volume":"8","author":"Jose","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1152\/japplphysiol.00039.2003","article-title":"Distribution and mitogen response of peripheral blood lymphocytes after exertional heat injury","volume":"95","author":"DuBose","year":"2003","journal-title":"J. Appl. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1152\/japplphysiol.00886.2003","article-title":"Exertional heat injury and gene expression changes: A DNA microarray analysis study","volume":"96","author":"Sonna","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The molecular signatures database (msigdb) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41418-018-0129-0","article-title":"c-Myc inhibits myoblast differentiation and promotes myoblast proliferation and muscle fibre hypertrophy by regulating the expression of its target genes, miRNAs and lincRNAs","volume":"26","author":"Luo","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1046\/j.1439-0388.1999.00200.x","article-title":"Associations between the c-myc proto-oncogene and carcass quality traits in the pig: Evidence for epistasis with the Ryr1-gene","volume":"116","author":"Reiner","year":"1999","journal-title":"J. Anim. Breed. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.bja.2019.02.010","article-title":"Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals","volume":"122","author":"Chang","year":"2019","journal-title":"Br. J. Anaesth."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Aldrich, K., Velez-Irizarry, D., Fenger, C., Schott, M., and Valberg, S.J. (2021). Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses. PLoS. ONE, 16.","DOI":"10.1371\/journal.pone.0244556"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1038\/s41467-020-18865-z","article-title":"Adaptive thermogenesis enhances the life-threatening response to heat in mice with an Ryr1 mutation","volume":"11","author":"Wang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s12630-020-01895-y","article-title":"Untargeted metabolomics profiling of skeletal muscle samples from malignant hyperthermia susceptible patients","volume":"68","author":"Bojko","year":"2021","journal-title":"Can. J. Anaesth."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1097\/ALN.0000000000000610","article-title":"Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness","volume":"122","author":"Fiszer","year":"2015","journal-title":"Anesthesiology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1001\/jama.286.2.168","article-title":"Malignant hyperthermia and apparent heat stroke","volume":"286","author":"Tobin","year":"2001","journal-title":"JAMA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41572-021-00334-6","article-title":"Classic and exertional heatstroke","volume":"8","author":"Bouchama","year":"2022","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1152\/japplphysiol.00316.2004","article-title":"Effects of exercise on gene expression in human peripheral blood mononuclear cells","volume":"97","author":"Connolly","year":"2004","journal-title":"J. Appl. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1152\/japplphysiol.00143.2013","article-title":"Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress","volume":"114","author":"Neubauer","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1152\/physiolgenomics.00096.2005","article-title":"cDNA microarray analysis reveals novel candidate genes expressed in human peripheral blood following exhaustive exercise","volume":"23","author":"Zieker","year":"2005","journal-title":"Physiol. Genom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9429","DOI":"10.1038\/s41598-017-09819-5","article-title":"A Model of Exposure to Extreme Environmental Heat Uncovers the Human Transcriptome to Heat Stress","volume":"7","author":"Bouchama","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.immuni.2019.09.006","article-title":"Butyrophilin-like 3 directly binds a human vgamma4(+) T cell receptor using a modality distinct from clonally-restricted antigen","volume":"51","author":"Willcox","year":"2019","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"43838","DOI":"10.1074\/jbc.M403612200","article-title":"Effect of Ryanodine Receptor Mutations on Interleukin-6 Release and Intracellular Calcium Homeostasis in Human Myotubes from Malignant Hyperthermia-susceptible Individuals and Patients Affected by Central Core Disease","volume":"279","author":"Ducreux","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1139\/H07-054","article-title":"The biological roles of exercise-induced cytokines: IL-6, IL-8, and IL-15","volume":"32","author":"Nielsen","year":"2007","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1152\/japplphysiol.00667.2016","article-title":"Unique cytokine and chemokine responses to exertional heat stroke in mice","volume":"122","author":"King","year":"2017","journal-title":"J. Appl. Physiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1152\/japplphysiol.00636.2013","article-title":"Heat stroke activates a stress-induced cytokine response in skeletal muscle","volume":"115","author":"Welc","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1113\/EP088501","article-title":"Acute phase response to exertional heat stroke in mice","volume":"106","author":"Iwaniec","year":"2020","journal-title":"Exp. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ren, M.Q., Kazman, J.B., Abraham, P.A., Atias-Varon, D., Heled, Y., and Deuster, P.A. (2019). Gene expression profiling of humans under exertional heat stress: Comparisons between persons with and without exertional heat stroke. J. Therm. Biol., 85.","DOI":"10.1016\/j.jtherbio.2019.102423"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bi, R., and Liu, P. (2016). Sample size calculation while controlling false discovery rate for differential expression analysis with RNA-sequencing experiments. BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-0994-9"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"10","DOI":"10.14806\/ej.17.1.200","article-title":"Cutadapt removes adapter sequences from high-throughput sequencing reads","volume":"17","author":"Martin","year":"2011","journal-title":"EMBnet J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1093\/nar\/gkp1137","article-title":"The Sanger FASTQ file format for sequences with quality scores, and the Solexa\/Illumina FASTQ variants","volume":"38","author":"Cock","year":"2009","journal-title":"Nucleic Acids. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Love, M.I., Huber, W., and Anders, S. (2014). Moderated estimation of fold change and dispersion for rna-seq data with deseq2. Genome Biol., 15.","DOI":"10.1186\/s13059-014-0550-8"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019Ayan, A. (2013). enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"100213","DOI":"10.1016\/j.patter.2021.100213","article-title":"Appyters: Turning Jupyter Notebooks into data-driven web apps","volume":"2","author":"Clarke","year":"2021","journal-title":"Patterns"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"J. R. Stat. Soc. Ser. B Methodol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16124\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:19:58Z","timestamp":1760131198000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/22\/16124"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,9]]},"references-count":46,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["ijms242216124"],"URL":"https:\/\/doi.org\/10.3390\/ijms242216124","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,9]]}}}