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