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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 knockout of calsequestrin-1 (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 journal : official publication of the Federation of American Societies for Experimental Biology
          FASEB
          1530-6860
          0892-6638
          May 02 2017
          Affiliations
          [1 ] Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), University G. d' Annunzio of Chieti, Chieti, Italy.
          [2 ] Department of Biomedical Sciences, University of Padova, Padua, Italy.
          [3 ] Center for Research on Ageing and Translational Medicine (CeSI-MeT), Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), University G. d' Annunzio of Chieti, Chieti, Italy; feliciano.protasi@unich.it.
          [4 ] Department of Medicine and Aging Science, University G. d' Annunzio of Chieti, Chieti, Italy.
          Article
          fj.201601292R
          10.1096/fj.201601292R
          28465322
          92fbefdf-df32-42ae-9b41-4bd103ad5427

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

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