Basis of Muscle Dysfunction in Malignant Hyperthermia & Central Core Disease

恶性高热中肌肉功能障碍的基础

• 批准号: 9904122
• 负责人: Robert T Dirksen
• 金额: $ 63.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904122
• 关键词: 21 year old; Acetylcysteine; Address; Age; Anesthetics; Antioxidants; Apoptosis; Area; Biotin; Butyrates; Central Core Myopathy; Cessation of life; Childhood; Clinical; Contracture; Dependence; Development; Disease; Estrogen receptor positive; Exercise; Exhibits; Fiber; Functional disorder; Heat Stress Disorders; Heat Stroke; Human; Immunoprecipitation; Intervention; Left; Life; Malignant hyperpyrexia due to anesthesia; Mass Spectrum Analysis; Mediating; Membrane Potentials; Metabolic; Mitochondria; Modeling; Modification; Molecular; Monitor; Multiminicore disease; Mus; Muscle; Muscle Fibers; Muscle function; Mutation; Myopathy; Names; Neuromuscular Depolarizing Agents; Oxidative Stress; Pathway interactions; Pharmaceutical Preparations; Phenotype; Phosphorylation; Post-Translational Protein Processing; Process; Production; Proteins; Puma; Reaction; Respiratory Failure; Rhabdomyolysis; Role; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Scientist; Severity of illness; Signal Transduction; Site-Directed Mutagenesis; Sudden Death; TP53 gene; Testing; Therapeutic Intervention; Wheelchairs; age related; base; congenital myopathy; cyclophilin D; design; disability; disease phenotype; endoplasmic reticulum stress; exercise capacity; improved; mitochondrial membrane; mitochondrial permeability transition pore; mouse model; multidisciplinary; novel therapeutic intervention; pifithrin; premature; public health relevance; receptor function; response; scoliosis; side effect

 DESCRIPTION (provided by applicant): Mutations in the type I ryanodine receptor (RyR1) are associated with a variety of human muscle diseases including malignant hyperthermia (MH), MH with cores, central core disease (CCD), multi-minicore disease, and others. RyR1-related myopathies are among the most common group of non-dystrophic muscle diseases and are associated with significant clinical disabilities, often including wheelchair dependence, severe scoliosis, respiratory failure, and can result in premature death in childhood. Currently there are no therapies for these devastating myopathies. MH mutations in RyR1 are frequently associated with heat stress, and/or exercise-induced heat stroke and/or rhabdomyolysis. CCD is a congenital myopathy associated with metabolically inactive central cores in skeletal muscle fibers, but the presence of cores is highly variable (despite the name) and the severity of the disease does not correlate with cores. We have shown that some CCD mutations increase Ca2+ leak from the sarcoplasmic reticulum, while others decrease Ca2+ permeation through RyR1. These finding raise the question of how opposing functional effects on RyR1 can result in related diseases. To answer this central, unresolved question and aid in the development of new interventions, we created mouse models of MH with cores (Y524S, YS) and CCD (I4895T, IT). Heterozygous YS mice are susceptible to anesthetic and heat-induced sudden death and also exhibit an age-dependent myopathy characterized by mitochondrial damage and the formation of amorphous cores. Heterozygous IT mice are not heat sensitive, but display decreased exercise capacity, deceased muscle fiber cross-sectional area, and a myopathy that increases with age. In this renewal application, we propose to define the cellular and molecular mechanisms by which functionally opposing RyR1 mutations produce these distinct phenotypes and then use these findings to develop new, mechanism-based therapeutic interventions for MH and CCD. Our working hypothesis is that the YS mutation drives the disease via increased RyR1 Ca2+ leak, activation of the mitochondrial permeability transition pore (mPTP), and oxidative stress, while the IT mutation enhances SR Ca2+ content, which leads to increased ER stress, p53 expression, mitochondrial damage and apoptosis. To test this hypothesis, we propose to: 1) Define the role of altered cytosolic, mitochondrial, and SR lumenal Ca2+ signaling and mPTP activation in the YS and IT myopathies. 2) Define the roles of RyR1 post- translational modifications. 3) Define the role of p53 in the IT myopathy and the enhanced heat sensitivity of YS mice. 4) Assess the potential of S107, NAC, 4PBA, and pifithrin-µ as interventions for MH and CCD. There are currently no therapies to treat RyR1-related myopathies. This multi-PI application is designed to address this need by carefully delineating specific cellular pathways that underlie disease processes and then to use this information to develop and test several novel therapeutic interventions with distinct mechanisms of action.

 描述（由申请人提供）：I型兰尼碱受体（RyR 1）的突变与多种人类肌肉疾病相关，包括恶性高热（MH）、MH伴核心、中央核心疾病（CCD）、多微核心疾病等。RyR 1相关的肌病是最常见的非营养不良性肌肉疾病之一，与严重的临床残疾有关，通常包括轮椅依赖、严重脊柱侧凸、呼吸衰竭，并可能导致儿童过早死亡。目前有 无法治疗这些毁灭性的肌病RyR 1中的MH突变通常与热应激和/或运动诱导的中暑和/或横纹肌溶解有关。CCD是一种先天性肌病，与骨骼肌纤维中代谢不活跃的中央核心有关，但核心的存在是高度可变的（尽管名称如此），疾病的严重程度与核心无关。我们已经表明，一些CCD突变增加Ca 2+从肌浆网泄漏，而其他减少Ca 2+透过RyR 1。这些发现提出了一个问题，即对RyR 1的相反功能影响如何导致相关疾病。为了回答这个核心的、未解决的问题并帮助开发新的干预措施，我们创建了具有核心（Y 524 S，YS）和CCD（I4895 T，IT）的MH小鼠模型。杂合子YS小鼠易受麻醉和热诱导的猝死，并且还表现出以线粒体损伤和无定形核心形成为特征的年龄依赖性肌病。杂合子IT小鼠对热不敏感，但表现出运动能力下降、肌纤维横截面积减少和随年龄增加的肌病。在这项更新申请中，我们建议定义功能上相反的RyR 1突变产生这些不同表型的细胞和分子机制，然后使用这些发现开发新的，基于机制的MH和CCD治疗干预措施。 我们的工作假设是YS突变通过增加RyR 1 Ca 2+泄漏、激活线粒体通透性转换孔（mPTP）和氧化应激来驱动疾病，而IT突变增强SR Ca 2+含量，这导致ER应激、p53表达、线粒体损伤和凋亡增加。为了验证这一假设，我们建议：1）确定改变的细胞溶质，线粒体和SR内腔Ca 2+信号和mPTP激活在YS和IT肌病中的作用。2)定义RyR 1翻译后修饰的作用。3)明确p53在YS小鼠IT肌病和热敏感性增强中的作用。4)评估S107、NAC、4PBA和pifithrin-µ作为MH和CCD干预措施的潜力。目前还没有治疗RyR 1相关肌病的疗法。这种多PI应用程序旨在通过仔细描绘疾病过程的特定细胞通路来满足这一需求，然后使用这些信息开发和测试具有不同作用机制的几种新型治疗干预措施。

项目成果

Malignant hyperthermia and the clinical significance of type-1 ryanodine receptor gene (RYR1) variants: proceedings of the 2013 MHAUS Scientific Conference.

• DOI: 10.1007/s12630-014-0227-5
• 发表时间: 2014-11
• 期刊: CANADIAN JOURNAL OF ANESTHESIA-JOURNAL CANADIEN D ANESTHESIE
• 影响因子: 4.2
• 作者: Riazi, Sheila;Kraeva, Natalia;Muldoon, Sheila M;Dowling, James;Ho, Clara;Petre, Maria-Alexandra;Parness, Jerome;Dirksen, Robert T;Rosenberg, Henry
• 通讯作者: Rosenberg, Henry

Ryanodine receptor 1-related disorders: an historical perspective and proposal for a unified nomenclature.

• DOI: 10.1186/s13395-020-00243-4
• 发表时间: 2020-11-16
• 期刊: Skeletal muscle
• 影响因子: 4.9
• 作者: Lawal TA;Todd JJ;Witherspoon JW;Bönnemann CG;Dowling JJ;Hamilton SL;Meilleur KG;Dirksen RT
• 通讯作者: Dirksen RT

Genomic Screening for Malignant Hyperthermia Susceptibility.

• DOI: 10.1097/aln.0000000000003547
• 发表时间: 2020-12-01
• 期刊: Anesthesiology
• 影响因子: 8.8
• 作者: Biesecker LG;Dirksen RT;Girard T;Hopkins PM;Riazi S;Rosenberg H;Stowell K;Weber J
• 通讯作者: Weber J

How mutations in RYR1 that cause malignant hyperthermia increase RYR1 sensitivity to activators.

导致恶性高热的 RYR1 突变如何增加 RYR1 对激活剂的敏感性。

• DOI: 10.1016/j.ceca.2021.102412
• 发表时间: 2021
• 期刊: Cell calcium
• 影响因子: 4
• 作者: Baker,MatthewL;Dirksen,RobertT;Hamilton,SusanL
• 通讯作者: Hamilton,SusanL