{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:17:38Z","timestamp":1790749058608,"version":"4.1.0"},"reference-count":80,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T00:00:00Z","timestamp":1505779200000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR053349\u201306"],"award-info":[{"award-number":["AR053349\u201306"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type\u20101 (RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    ) and calsequestrin\u20101 knockout (CASQ1\u2010null), 2 proteins that control Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    and CASQ1\u2010null mice to an exertional\u2010stress protocol (incremental running on a treadmill at 34\u00b0C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    and CASQ1\u2010null mice, respectively, vs. 0% in wild\u2010type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    and CASQ1\u2010null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca\n                    <jats:sup>2+<\/jats:sup>\n                    dependent activation of calpains and NF\u2010kB by lowering myoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    concentration and nitro\u2010oxidative stress, parameters that were elevated in RYR1\n                    <jats:sup>Y522S\/WT<\/jats:sup>\n                    and CASQ1\u2010null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.\u2014Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life\u2010threatening response in mice susceptible to malignant hyperthermia.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 31, 3649\u20133662 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201601292r","type":"journal-article","created":{"date-parts":[[2017,5,2]],"date-time":"2017-05-02T20:35:16Z","timestamp":1493757316000},"page":"3649-3662","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Strenuous exercise triggers a life\u2010threatening response in mice susceptible to malignant hyperthermia"],"prefix":"10.1096","volume":"31","author":[{"given":"Antonio","family":"Michelucci","sequence":"first","affiliation":[{"name":"Center for Research on Ageing and Translational Medicine (CeSI\u2010MeT) Department of Neuroscience, Imaging, and Clinical Sciences (DNICS) University G. d\u2019 Annunzio of Chieti  Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Paolini","sequence":"additional","affiliation":[{"name":"Center for Research on Ageing and Translational Medicine (CeSI\u2010MeT) Department of Neuroscience, Imaging, and Clinical Sciences (DNICS) University G. d\u2019 Annunzio of Chieti  Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Boncompagni","sequence":"additional","affiliation":[{"name":"Center for Research on Ageing and Translational Medicine (CeSI\u2010MeT) Department of Neuroscience, Imaging, and Clinical Sciences (DNICS) University G. d\u2019 Annunzio of Chieti  Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Canato","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Reggiani","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences University of Padova  Padua Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feliciano","family":"Protasi","sequence":"additional","affiliation":[{"name":"Center for Research on Ageing and Translational Medicine (CeSI\u2010MeT) Department of Neuroscience, Imaging, and Clinical Sciences (DNICS) University G. d\u2019 Annunzio of Chieti  Chieti Italy"},{"name":"Department of Medicine and Aging Science University G. d\u2019 Annunzio of Chieti  Chieti Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,9,19]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/34.6.395"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.296.6634.1442-a"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1589759"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI111057"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl077"},{"key":"e_1_2_13_7_1","doi-asserted-by":"crossref","DOI":"10.1002\/humu.9442","article-title":"Frequency and localization of mutations in the 106 exons of the RYR1 gene in 50 individuals with malignant hyperthermia","volume":"27","author":"Galli L.","year":"2006","journal-title":"Hum. Mutat."},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1997.77.3.699"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ph.56.030194.002335"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.4065\/70.3.241"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00131402-200212000-00004"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aeq243"},{"key":"e_1_2_13_13_1","first-page":"1267","article-title":"A protocol for the investigation of malignant hyperpyrexia (MH) susceptibility","volume":"56","year":"1984","journal-title":"The European Malignant Hyperpyrexia Group. Br. J. Anaesth"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1213\/00000539-198910000-00015"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/6.6.953"},{"key":"e_1_2_13_16_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-015-0310-1","article-title":"Malignant hyperthermia: a review","volume":"10","author":"Rosenberg H.","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1086\/515454"},{"key":"e_1_2_13_18_1","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2350-10-104","article-title":"The role of CACNA1S in predisposition to malignant hyperthermia","volume":"10","author":"Carpenter D.","year":"2009","journal-title":"BMC Med. Genet."},{"key":"e_1_2_13_19_1","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-2-21","article-title":"Malignant hyperthermia","volume":"2","author":"Rosenberg H.","year":"2007","journal-title":"Orphanet J. Rare Dis."},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aer132"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra011089"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(91)92304-K"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318232008f"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/88.4.508"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.286.2.168"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181c29504"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3182320068"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-197201000-00009"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-197201000-00008"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-4497fje"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200612000-00016"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.02.042"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.138024"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-121335"},{"key":"e_1_2_13_35_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2009.171967"},{"key":"e_1_2_13_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.anes.0000530185.78660.da"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22631"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2014-102882"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000748"},{"key":"e_1_2_13_40_1","doi-asserted-by":"crossref","DOI":"10.1186\/s13395-015-0035-9","article-title":"Oxidative stress, mitochondrial damage, and cores in muscle from calsequestrin\u20101 knockout mice","volume":"5","author":"Paolini C.","year":"2015","journal-title":"Skelet. Muscle"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1472-8206.2009.00787.x"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.20177"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009168108"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(72)90094-2"},{"key":"e_1_2_13_45_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1177\/0310057X9802600317","article-title":"Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia","volume":"26","author":"K\u00f6chling A.","year":"1998","journal-title":"Anaesth. Intensive Care"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200101000-00019"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0911496106"},{"key":"e_1_2_13_48_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.21.12100"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2002"},{"key":"e_1_2_13_50_1","first-page":"181","article-title":"Biomarkers of oxidative\/ nitrosative stress: an approach to disease prevention","volume":"61","author":"Ogino K","year":"2007","journal-title":"Acta Med. Okayama"},{"key":"e_1_2_13_51_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0542com"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.178"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/0306-9877(95)90116-7"},{"key":"e_1_2_13_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)31728-9"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(02)75396-4"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.90642.2007"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-187252"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-197503000-00011"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF03006495"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199109000-00006"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.104976"},{"key":"e_1_2_13_62_1","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0077633","article-title":"Accelerated activation of SOCE current in myotubes from two mouse models of anesthetic\u2010 and heat\u2010induced sudden death","volume":"8","author":"Yarotskyy V.","year":"2013","journal-title":"PLoS One"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3260847"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.43.26965"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.31.18465"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.105.084046"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M408375200"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.107.043299"},{"key":"e_1_2_13_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2010.06.050"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602306200"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02034655"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(99)00095-3"},{"key":"e_1_2_13_73_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.2009.05310.x"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.151.7.1583"},{"key":"e_1_2_13_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4598(200001)23:1<106::AID-MUS14>3.0.CO;2-D"},{"key":"e_1_2_13_76_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.21.2645"},{"key":"e_1_2_13_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2010.06.025"},{"key":"e_1_2_13_78_1","doi-asserted-by":"publisher","DOI":"10.1097\/MCO.0b013e328352b4c2"},{"key":"e_1_2_13_79_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.344929"},{"key":"e_1_2_13_80_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-8966(97)00124-7"},{"key":"e_1_2_13_81_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2015.03.012"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201601292R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1096\/fj.201601292R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.201601292R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T23:21:56Z","timestamp":1761693716000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.201601292R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8]]},"references-count":80,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1096\/fj.201601292R"],"URL":"https:\/\/doi.org\/10.1096\/fj.201601292r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8]]},"assertion":[{"value":"2016-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-04-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-09-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}