Environmental and Epigenetic Modifiers of Susceptibility to Malignant Hyperthermia and Environmental Heat Stroke

骨骼肌（SkM）肌浆网（SR）Ca 2+释放通道（Ryanodine受体）突变 1型，RYR 1），控制SkM兴奋-收缩偶联的大分子复合物的一种成分 (ECC)是恶性高热敏感性（MHS）和环境热的已知遗传原因 疾病/环境中暑（EHI/EHS）。MHS/EHS表现出不完全的外显率，可变的表达度 和不和谐的遗传造成这种差异的原因仍然是个谜。没有有效的治疗方法 对于患有RYR 1致病性变异的个体，在非正常情况下发生危及生命的MHS/EHS事件， 临床环境（发热儿科患者、运动员、高温环境中的军事人员）。 我们的目标是开发预防与RYR 1致病性变异相关的EHI相关死亡的方法。 我们提出存在一个环境敏感，表观遗传调节，反馈回路之间 SkM和BAT使MHS人类和小鼠对热敏感。我们的具体假设是：1）热量和 增加的SkM活性驱动SkM和BAT中的代谢和表观遗传变化， MHS小鼠。2)MHS小鼠体温升高可增强SR Ca 2+渗漏、乳酸产生和AMPK SkM中的活化和代谢变化，这反过来又驱动SkM和BAT中的表观遗传修饰， 进一步增强对热的敏感性。3)热驱动的表观遗传变化具有性别偏见和遗传性， 这些假设将在3个特定目标中进行检验。具体目标1：确定角色 热、糖酵解、乳酸和适应性产热在MHS/EHS小鼠对热的敏感性增强中的作用。 具体目标2：确定SKM中RyR 1 Ca 2+泄漏和AMPK激活对增强的敏感性的作用。 MHS小鼠加热。具体目标3：确定由热驱动的表观遗传变化是否可遗传和性别偏见。 这些研究的完成将阐明基本的分子和表观遗传机制， EHS的表达率，表达率和遗传不一致性的变异，以及提供关于 环境和遗传在这些疾病中的复杂相互作用。这些数据将导致一个新的认识 EHS事件的驱动因素，并最终制定预防策略。

Mutations in the skeletal muscle (SkM) sarcoplasmic reticulum (SR) Ca2+ release channel (Ryanodine Receptor Type 1, RYR1), a component of the macromolecular complex that controls SkM excitation- contraction coupling (ECC), are known genetic causes of Malignant Hyperthermia sensitivity (MHS) and Environmental Heat Illness/Environmental Heat Stroke (EHI/EHS). MHS/EHS display incomplete penetrance, variable expressivity and discordant inheritance. The reasons for this variability remain enigmatic. There are no effective treatments for individuals with RYR1 pathogenic variants who experience life-threatening MHS/EHS episodes outside of clinical settings (febrile pediatric patients, athletes, military personnel in hot environments). Our goal is to develop approaches to prevent EHI-related deaths associated with RYR1 pathogenic variants. We propose the existence of an environmentally sensitive, epigenetically regulated, feedback loop between SkM and BAT that sensitizes MHS humans and mice to heat. Our specific hypotheses are: 1) Heat and increased SkM activity drive metabolic and epigenetic changes in SkM and BAT to increase thermogenesis in MHS mice. 2) Increased body temperature in MHS mice enhances SR Ca2+ leak, lactate production, AMPK activation and metabolic changes in SkM, which, in turn, drive epigenetic modifications in SkM and BAT that further enhance sensitivity to heat. 3) Heat-driven epigenetic changes are sex-biased and heritable and contribute to discordance These hypotheses will be tested in 3 Specific Aims. Specific Aim 1: Define the roles of heat, glycolysis, lactate, and adaptive thermogenesis in the enhanced sensitivity of MHS/EHS mice to heat. Specific Aim 2: Define the role of RyR1 Ca2+ leak and AMPK activation in SKM on the enhanced sensitivity of MHS mice to heat. Specific Aim 3: Determine if epigenetic changes driven by heat are heritable and sex biased. Completion of these studies will elucidate fundamental molecular and epigenetic mechanisms that underlie variability in EHS penetrance, expressivity, and genetic discordance, as well as provide new information on the complex interplay of environment and genetics in these disorders. These data will lead to a new understanding of the drivers of EHS episodes and, ultimately, to strategies for their prevention.