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      Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia

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          Abstract

          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-1 (RYR1 Y522S/WT) and calsequestrin-1 knockout (CASQ1-null), 2 proteins that control Ca 2+ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1 Y522S/WT and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1 Y522S/WT and CASQ1-null mice, respectively, vs. 0% in wild-type 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 Y522S/WT and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca 2+-dependent activation of calpains and NF-κB by lowering myoplasmic Ca 2+ concentration and nitro-oxidative stress, parameters that were elevated in RYR1 Y522S/WT and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.—Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.

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          Author and article information

          Journal
          FASEB J
          FASEB J
          fasebj
          fasebj
          FASEB
          The FASEB Journal
          Federation of American Societies for Experimental Biology (Bethesda, MD, USA )
          0892-6638
          1530-6860
          August 2017
          02 May 2017
          1 August 2018
          : 31
          : 8
          : 3649-3662
          Affiliations
          [* ]Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), Università degli Studi G. d’Annunzio, Chieti, Italy;
          []Department of Biomedical Sciences, University of Padova, Padua, Italy;
          []Department of Medicine and Aging Science, University G. d’ Annunzio of Chieti, Chieti, Italy
          Author notes
          [1 ]Correspondence: CeSI-MeT, Center for Research on Aging and Translational Medicine, University G. d’Annunzio of Chieti, I-66100 Chieti, Italy. E-mail: feliciano.protasi@ 123456unich.it
          Article
          PMC5503704 PMC5503704 5503704 FJ_201601292R
          10.1096/fj.201601292R
          5503704
          28465322
          92fbefdf-df32-42ae-9b41-4bd103ad5427
          © FASEB
          Page count
          Figures: 8, Tables: 0, Equations: 0, References: 80, Pages: 14
          Categories
          Research
          Custom metadata
          v1

          calsequestrin-1,excitation-contraction coupling,ryanodine receptor,sarcoplasmic reticulum,skeletal muscle

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