The Role of Cardiomyopathic Troponin C Mutations in Skeletal and Cardiac Muscle C

心肌病肌钙蛋白 C 突变在骨骼肌和心肌 C 中的作用

基本信息

批准号：
8528011
负责人：
Jose Renato Pinto
金额：
$ 24.9万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-20 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528011
关键词：
ATP phosphohydrolase Actomyosin Address Affect Affinity Arrhythmia Binding Body Weight Buffers Calcium Cardiac Cardiac Muscle Contraction Cardiomyopathies Chelating Agents Circular Dichroism Complex Congestive Heart Failure Development Dilated Cardiomyopathy Disease Dissociation Fiber Fibrosis Fluorescence Functional disorder Generations Genes Grant Heart Heart Diseases Hereditary Disease Hypertrophic Cardiomyopathy In Situ In Vitro Investigation Kinetics Knock-in Mouse Knowledge Label Laboratories Lead Link Measurement Measures Microfilaments Molecular Monitor Morphology Muscle Muscle Cells Muscle Contraction Muscle Fibers Mutation Myocardium Myopathy Papillary Patients Phenotype Physiological Play Process Property Proteins Recombinants Regulation Relaxation Reporting Role Skeletal Muscle Skeletal system Skin Soleus Muscle Striated Muscles Structure System Thick Filament Thin Filament Troponin Troponin C Troponin I Troponin T Ventricular in vivo innovation insight mouse model mutant novel strategies protein protein interaction reconstitution research study sensor skeletal skeletal abnormality stopped-flow fluorescence sudden cardiac death therapeutic development

项目摘要

Project Summary The cardiac troponin complex (CTn) is made up of cardiac troponin T (CTnT), that attaches the complex to the thin filament; cardiac troponin I (CTnI), involved in the inhibition of muscle contraction and cardiac/slow skeletal troponin C (CTnC), that binds Ca2+ and triggers contraction. Altogether, the CTn, regulates muscle contraction, i.e., Ca2+ sensitivity of force development, maximal force development and basal force. Cardiac/Slow Skeletal Troponin C (C/SSTnC) is the only component of CTn that is expressed and present in both cardiac and slow skeletal muscles. It is considered the primary Ca2+ sensor of striated muscle and has been a target of Hypertrophic (HCM) and Dilated (DCM) Cardiomyopathies. HCM or DCM are genetic disorders caused by the mutations in the TnC gene that are characterized by morphological changes in the ventricular walls and altered Ca2+ handling of the diseased heart. HCM mutations in troponin cause the cardiac myofilament to become sensitized to Ca2+ which is implicated as causing arrhythmias and sudden cardiac death. In contrast, troponin mutations related to DCM desensitize myofilaments to Ca2+ which often leads to congestive heart failure. CTn mutations related to cardiomyopathy have been extensively studied in the cardiac system. However, the functional consequences of cardiomyopathic C/SSTnC mutants also present in slow skeletal muscle are unknown. The question to be addressed in this grant is: What are the functional consequences of C/SSTnC mutations linked to HCM and DCM in the regulation of slow skeletal muscle contraction? How do they compare to those found in cardiac muscle? To accomplish this, in vitro systems will be utilized as well as skinned fibers which will be used to measure the force/pCa relationship. These measurements will be performed in both skeletal and cardiac muscles. An HCM CTnC knock-in mouse generated in the laboratory will be characterized to determine the in vivo consequences of the mutation in intact and skinned fibers. The aims of this proposal address the functional differences that underlie the phenotypes of C/SSTnC mutations in cardiac and skeletal muscles. These studies will investigate whether slow skeletal muscle containing C/SSTnC mutations develops skeletal abnormalities similar to those seen in the heart and whether the function of skeletal muscle is altered in the mutation-knock in mouse model. The questions that are being addressed are: Is the change that occurs in the skeletal system comparable to changes that occur in cardiac muscle? If the functional changes in slow skeletal muscle appear minimal what additional components absent in the regulation of cardiac muscle assist in rescuing the effects of the mutation? Successful execution of these aims will lead to a better understanding of cardiac versus slow skeletal muscle disorders associated with mutations in the TnC gene.

项目概要心肌肌钙蛋白复合物 (CTn) 由心肌肌钙蛋白 T (CTnT) 组成，将复合到细丝；心肌肌钙蛋白 I (CTnI)，参与抑制肌肉收缩以及心脏/慢骨骼肌钙蛋白 C (CTnC)，它与 Ca2+ 结合并触发收缩。总而言之， CTn，调节肌肉收缩，即力量发展的 Ca2+ 敏感性、最大力量发育和基础力。心脏/慢骨骼肌钙蛋白 C (C/SSTnC) 是唯一的成分 CTn 在心肌和慢骨骼肌中表达和存在。它被认为是横纹肌的主要 Ca2+ 传感器，一直是肥厚 (HCM) 和扩张的目标 (DCM) 心肌病。 HCM 或 DCM 是由 TnC 突变引起的遗传性疾病以心室壁形态变化和 Ca2+ 改变为特征的基因处理患病的心脏。肌钙蛋白的 HCM 突变导致心肌丝变得对 Ca2+ 敏感，这可能导致心律失常和心源性猝死。相比之下，与 DCM 相关的肌钙蛋白突变使肌丝对 Ca2+ 不敏感，这通常会导致充血心脏衰竭。与心肌病相关的 CTn 突变已在心脏疾病中得到广泛研究。系统。然而，心肌病 C/SSTnC 突变体的功能后果也慢骨骼肌中存在的物质尚不清楚。这笔赠款要解决的问题是：什么是与 HCM 和 DCM 相关的 C/SSTnC 突变在调节中的功能性后果骨骼肌收缩缓慢？它们与心肌中发现的相比如何？到为了实现这一目标，将利用体外系统以及皮纤维，该纤维将用于测量力/pCa 关系。这些测量将在骨骼和心肌。实验室生成的 HCM CTnC 敲入小鼠将具有以下特点：确定完整纤维和带皮纤维突变的体内后果。本次活动的目的该提案解决了 C/SSTnC 突变表型背后的功能差异心脏和骨骼肌。这些研究将调查慢速骨骼肌是否含有 C/SSTnC 突变会导致与心脏相似的骨骼异常，以及是否在小鼠模型中，骨骼肌的功能在突变敲除中发生了改变。提出的问题正在解决的问题是：骨骼系统中发生的变化是否与身体变化具有可比性发生在心肌中？如果慢骨骼肌的功能变化看起来很小，那么什么心肌调节中缺少的其他成分有助于挽救心肌的影响突变？成功执行这些目标将有助于更好地理解心脏与与 TnC 基因突变相关的慢性骨骼肌疾病。