Slow myosin binding protein-C in skeletal muscle physiology

骨骼肌生理学中的慢肌球蛋白结合蛋白-C

基本信息

批准号：
10461813
负责人：
Sakthivel Sadayappan
金额：
$ 46.13万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10461813
关键词：
ATP phosphohydrolase Ablation Actins Actomyosin Address Adult Arthrogryposis Birth Calcium Cardiac Myosins Classification Clinical Contracture DNA Sequence Alteration Data Development Disease Disease Progression Distal Exhibits Fiber Functional disorder Gene Mutation Genes Genetic Goals Health Histopathology Human Impairment In Vitro Intervention Joints Kinetics Knockout Mice Lead Light Link Live Birth MM form creatine kinase Mediating Molecular Mus Muscle Muscle Development Muscle Weakness Muscle function Muscular Atrophy Mutation Myopathy Myosin ATPase Outcome Pathologic Penetrance Perinatal Phenotype Physical therapy Physiological Post-Translational Protein Processing Protein Family Protein Isoforms Proteins Regulation Research Respiration Disorders Respiratory Diaphragm Respiratory Muscles Role Sarcomeres Secondary to Signal Pathway Signal Transduction Skeletal Muscle Skeletal Muscle Myosins Soleus Muscle Striated Muscles Syndrome Tamoxifen Testing Transgenic Mice Tremor Variant Wild Type Mouse base citrate carrier defined contribution experimental study extensor digitorum improved in vivo insight mouse model muscle physiology muscular structure myosin-binding protein C new therapeutic target novel overexpression paralogous gene perinatal development perinatal period postnatal prenatal programs promoter pup skeletal skeletal muscle weakness therapeutic target translational study wasting

项目摘要

PROJECT SUMMARY: The distal arthrogryposes (DA) are a heterogeneous group of disorders characterized by congenital nonprogressive joint contractures associated with muscle weakness. Depending on the gene involved and the specific mutation, inheritance is typically autosomal dominant with variable expression and incomplete penetrance. Current clinical classification identifies eleven different discrete syndromes with several associated with mutations in sarcomere genes including slow skeletal myosin binding protein-C (MYBPC1). Recently, a homozygous recessive mutation in MYBPC1 was linked to a severe form of DA, lethal congenital contracture syndrome type 4 (LCCS4). Despite the increasing association of DA syndromes with specific genetic mutations, molecular mechanisms that underlie skeletal muscle weakness that presumably lead to disabling contractures are poorly understood. As these mechanisms are unknown and, specifically, little is known about how sMyBP-C regulates muscle function in vivo, current therapies are largely ineffective and relegated to symptomatic physical therapy. The overall long-term goal of our research program has been to define the contribution of the myosin binding protein-C (MyBP-C) proteins in health and disease. These sarcomeric-specific proteins are known to regulate striated muscle contractility via modulating actomyosin function. Three MyBP-C paralogs exist, namely slow skeletal MyBP-C (sMyBP-C), fast skeletal (fMyBP-C), and cardiac MyBP-C, and encoded by separate genes. The specific goal of this proposal is to define the physiologic mechanisms underlining how mutations in sMyBP- C lead to muscle dysfunction and contractures. In our preliminary studies, we determined that mouse pups that are homozygous global sMyBP-C null (Mybpc1-/-), similar to the human LCCS4 phenotype, all died within the first day of birth and exhibited tremors secondary to muscle atrophy. We demonstrated that muscle creatine kinase Cre- and human a-skeletal actin-Cre/Tamoxifen-mediated sMyBP-C ablation (Mybpc1fl/fl) resulted in significant muscle weakness in postnatal and adult stages, respectively. Finally, we showed in transgenic mice overexpressing Mybpc1Tg under the control of the human a-skeletal actin promoter that sMyBP-C replaces fMyBP-C impairing fast muscle type function. Based on these data, we hypothesize that sMyBP-C acts as a key regulator of striated muscle formation and function in both slow and fast muscle types. The planned experiments will systematically define whether (i) sMyBP-C is essential for normal formation of muscle in prenatal and perinatal stages, (ii) sMyBP-C is required for skeletal muscle function in postnatal and adult stages, and (iii) sMyBP-C and fMyBP-C transcomplement each other. We anticipate that addressing these key questions will drive mechanistic understanding of how sMyBP-C regulates skeletal muscle physiology across developmental stages. Consequently, this proposal will identify therapeutic targets to improve muscle function in those afflicted with DA diseases.

项目摘要：远端节肢动物（DA）是一组异质的疾病。通过先天性非进化联合缔约，与肌肉无力相关。取决于基因涉及和特定的突变，遗传通常是常染色体显性，具有可变的表达和不完整的外渗。当前的临床分类鉴定了11种不同的离散综合症与肉瘤基因中的突变有关，包括缓慢的骨骼肌球蛋白结合蛋白-C（MYBPC1）。最近，MyBPC1中的纯合隐性突变与严重的DA，致命的先天性有关鉴定综合征4型（LCCS4）。尽管DA综合征与特定遗传的关系增加了突变，基于骨骼肌无力的分子机制，可能导致残疾缔约方知之甚少。由于这些机制是未知的，具体来说，关于 SMYBP-C如何调节体内肌肉功能，当前疗法在很大程度上无效，并降级为有症状的物理治疗。我们研究计划的总体长期目标是定义肌球蛋白结合的贡献健康和疾病中的蛋白质-C（MYBP-C）蛋白质。已知这些肉类特异性蛋白会调节通过调节肌动蛋白功能，横纹肌肉收缩力。存在三个MYBP-C旁系同源物，即慢慢骨骼MYBP-C（SMYBP-C），快速骨骼（FMYBP-C）和心脏MYBP-C，并由单独的基因编码。该提案的具体目标是定义强调SMYBP-突变的生理机制 C导致肌肉功能障碍和染色。在我们的初步研究中，我们确定了小鼠与人类LCCS4表型相似出生的第一天，表现出肌肉萎缩为继发的震颤。我们证明了肌肉肌酸激酶Cre-和人A-骨骼肌动蛋白-CRE/他莫昔芬介导的SMYBP-C消融（MyBPC1FL/FL）导致产后和成人阶段的肌肉无力。最后，我们在转基因小鼠中显示在人类A骨骼肌动蛋白启动子的控制下过表达MyBPC1TG，Smybp-c替换 FMYBP-C损害快速肌肉类型功能。基于这些数据，我们假设SMYBP-C充当横纹肌形成和在慢速和快速肌肉类型中起作用。计划的实验将系统地定义（i）是否存在 SMYBP-C对于在产前和围产期阶段的正常形成是必不可少的，（ii）SMYBP-C是必不可少的用于产后和成人阶段中的骨骼肌功能，以及（iii）SMYBP-C和FMYBP-C进行。彼此。我们预计解决这些关键问题将推动机械理解 SMYBP-C调节跨发育阶段的骨骼肌生理。因此，该提议将确定治疗靶标，以改善患有DA疾病的患者的肌肉功能。