Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca²⁺ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations.

中文翻译：

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膳食咖啡因可协同恶性高热易感小鼠对麻醉的不良外周和中枢反应。

Ryanodine 受体 ( RYR ) 突变赋予应激触发的恶性高热 (MH) 易感性。膳食咖啡因 (CAF) 是人类最常食用的精神活性化合物。CAF 触发的 Ca ²⁺释放及其对骨骼肌收缩力的影响被广泛用作研究 RYR 功能/功能障碍和诊断 MH 易感性的实验工具。我们假设饮食 CAF 达到人体血浆中测量的血液水平会加剧RYR1的外显率由气体麻醉剂触发的 MH 易感性突变，影响中枢和外周不良反应。杂合 R163C-RYR1 (HET) MH 易感小鼠用于在维持正常核心体温的实验条件下研究膳食 CAF 对诱导氟烷 (HAL) 维持麻醉前后外周和中枢反应的影响。与野生型相比，接受 CAF（血浆 CAF 893 ng/ml）的 HET 小鼠呼吸停止的时间显着缩短，不会改变血液化学或表现出体温过高或肌肉僵硬。HAL 前腹腔注射丹曲林可延长呼吸停止时间。一项使用皮下电极的试点电图研究表明，饮食 CAF 不会改变基线脑电图 (EEG) 总功率，但显着缩短了等电 EEG 的延迟，该延迟在呼吸和心脏骤停之前。CAF ± HAL 在 RYR1 单通道电流和 HET 肌管上进行研究，以定义基因与环境协同作用的分子机制。CAF 和 HAL 之间的强药理协同作用在单通道和肌管制剂中均得到证实。在暴露于膳食 CAF 的 MH 易感性 HET 模型中，中枢和外周神经系统介导对 HAL 的不良反应，这是一种可改变的生活方式因素，可降低与 CAF 和 HAL 之间的强药理协同作用在单通道和肌管制剂中均得到证实。在暴露于膳食 CAF 的 MH 易感性 HET 模型中，中枢和外周神经系统介导对 HAL 的不良反应，这是一种可改变的生活方式因素，可以降低与 CAF 和 HAL 之间的强药理协同作用在单通道和肌管制剂中均得到证实。在暴露于膳食 CAF 的 MH 易感性 HET 模型中，中枢和外周神经系统介导对 HAL 的不良反应，这是一种可改变的生活方式因素，可降低与RYR1突变。