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Novel Interventions for Heat/Exercise Induced Sudden Death and Fatigue

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Annual rept. 1 Oct 2012-30 Sep 2013

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Our goal is to identify ryanodine receptor type 1 RYR1, calcium channel, voltage-dependent, L type, alpha 1S subunit CACNA1S, and calsequestrin 1 CASQ1 gene mutations associated with enhanced susceptibility to Exertional Heat Stroke EHS, Exertional Rhabdomyolysis ER, and Malignant Hyperthermia MH by enrolling subjects diagnosed with these conditions and performing genetic screening. During the project period, 8 additional subjects were enrolled, bringing the total to 45 32 index cases and 13 family members from 3 of the index cases. Of the 32 index cases, 7 subjects have known MH-causative RYR1 gene mutations Arg163Cys, Gly2434Arg, Arg2454Cys, Arg2163His, and Ala2350Thr, 2 have known MH-associated RYR1 variants, 3 have novel RYR1 variants, 14 have no RYR1 mutations or variants, and 2 are still in progress. One subject had a known MH-causative mutation and a novel variant. Of the 13 family members screened from 3 index cases, 7 family members were found to share the same known MH-causative RYR1 gene mutation. Of the known MH-causative mutations, the Arg2454Cys was identified in an African American with a positive CHCT and a history of ER. Identification of this mutation in a subject with ER strengthens the link between MHS and ER. Although we have not yet found an AICAR derivative that prevents the hypermetabolic response in mice, we have recently explored the use of other drugs that can reduce RyR1 leak. One such drug is rapamycin. We have shown that rapamycin reduces the probability of a hypermetabolic response in YS mice.

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  • Anatomy and Physiology
  • Medicine and Medical Research
  • Stress Physiology

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