Basis of Muscle Dysfunction in Malignant Hyperthermia and Central Core Disease

描述（由申请人提供）：RYR1基因突变是几种使人衰弱、危及生命的肌肉疾病的基础。在这项申请中，我们建议使用RyR1 （Y524S）敲入突变的小鼠模型，该模型具有以下三种疾病的特征：恶性高热（MH）、热/运动诱导的运动性横纹肌溶解（ER）和中央核心疾病（CCD）。我们的长期目标是确定与这些疾病相关的肌肉功能下降的机制，并开发新的干预措施。我们目前提出的总体工作假设是，RyR1中的Y524S突变增加了兴奋-收缩耦合（ECC）和RyR1 Ca2+泄漏的温度敏感性，产生MH反应并驱动氧化应激和线粒体破坏，导致肌病。我们的具体目标是：1)阐明Ca2+内流通过CaV1.1在MH反应和肌病发展中的作用；2)描述YS小鼠核形成机制；3)明确能量感应激酶AMPK的激活剂（AICAR）阻止MH反应的机制，并评估AICAR减缓YS小鼠肌病发展的能力；4)明确FKBP12蛋白的非免疫抑制配体阻止MH反应的机制，评价SLF对YS小鼠肌病的影响。这项工作非常重要，因为我们直接将疾病过程的途径描述与具有不同作用机制的新型治疗干预措施的发展联系起来，从而允许一些灵活性来定制与MH和CCD相关的不同突变的治疗策略。本研究的创新之处在于：1)范式转换假设；2)独特的小鼠模型，3)尖端技术，以及4)治疗干预从未被提出用于治疗MH或其他ryr1相关的肌病。

DESCRIPTION (provided by applicant): Mutations in the RYR1 gene underlie several debilitating, life-threatening muscle diseases. In this application we are proposing to use a mouse model with a knockin mutation into RyR1 (Y524S) that has features of three of these disorders: malignant hyperthermia (MH) heat/exercise-induced exertional rhabdomyolysis (ER) and central core disease (CCD). Our long term goals are to define the mechanisms that underlie the decline in muscle function associated with these diseases and to develop new interventions. Our overall working hypothesis for the current proposal the Y524S mutation in RyR1 increases the temperature sensitivity of both excitation-contraction coupling (ECC) and RyR1 Ca2+ leak, producing the MH response and driving oxidative stress and mitochondrial destruction that leads to the myopathy. Our specific aims are to: 1) Elucidate the role of Ca2+ influx via CaV1.1 in the MH response and the development of the myopathy; 2) Delineate the mechanisms of core formation in YS mice; 3) Define the mechanism by which an activator (AICAR) of the energy sensing kinase AMPK prevents the MH response and evaluate AICAR's ability to slow the development of the myopathy in YS mice; and 4) Define the mechanism by which a non-immunosuppressive ligand for the protein FKBP12 prevents the MH response and evaluate SLF's effect on the myopathy in YS mice. The proposed work is highly significant because we directly couple the delineation of pathways underlying disease processes with the development of novel therapeutic interventions that have distinct mechanisms of action, allowing for some flexibility to tailor treatment strategies to different mutations associated with MH and CCD. The proposed research is innovative because of: 1) paradigm shifting hypotheses; 2) unique mouse models, 3) cutting edge technologies, and 4) therapeutic interventions never previously proposed as treatments for MH or other RyR1-linked myopathies.