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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：
10239247
负责人：
Sakthivel Sadayappan
金额：
$ 45.2万
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/10239247
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 Structure 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.

项目总结：远端关节挛缩（DA）是一种异质性疾病