Molecular Dissection of Myoblast Fusion In Muscle Development and Regeneration

肌肉发育和再生中成肌细胞融合的分子解剖

• 批准号: 9301471
• 负责人: RHONDA BASSEL-DUBY
• 金额: $ 35.64万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301471
• 关键词: Actins; Adult; Cell Culture Techniques; Cell fusion; Cell surface; Cells; Chimeric Proteins; Cytoskeleton; Development; Disease; Dissection; Drosophila genus; Embryo; Embryonic Development; Family; Fibroblasts; Foundations; Gene Deletion; Genetic; Glean; Goals; Injury; Knowledge; Laboratories; Light; Membrane; Membrane Proteins; Molecular; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle Proteins; Muscle satellite cell; Mutagenesis; Myoblasts; Myopathy; Names; Natural regeneration; Perinatal mortality demographics; Pharmacology; Process; Proteins; Reagent; Signal Transduction; Skeletal Muscle; Specificity; Structure; System; Testing; Work; base; cell type; insight; interest; loss of function; muscle regeneration; novel; novel therapeutic intervention; novel therapeutics; overexpression; prevent; public health relevance; response to injury; restoration; satellite cell

 DESCRIPTION (provided by applicant): The formation of skeletal muscle during embryonic development and following injury to adult muscle requires fusion of myoblasts to form multinucleated myofibers. Recently, we discovered a novel muscle-specific membrane protein, named Myomaker, that controls vertebrate myoblast fusion during embryogenesis and adulthood. Myomaker is expressed on the cell surface of embryonic myoblasts during fusion and is down- regulated thereafter. Similarly, Myomaker is up-regulated in muscle satellite cells in response to injury, concomitant with their fusion during muscle regeneration. Over-expression of Myomaker in myoblasts dramatically enhances fusion and forced expression in fibroblasts promotes fusion with myoblasts. Conversely, genetic disruption of Myomaker in mice causes perinatal death due to an absence of multi- nucleated muscle fibers and conditional gene deletion in adult satellite cells completely prevents muscle regeneration. The discovery of Myomaker provides a new inroad into myoblast fusion and will enable the detailed molecular dissection of the mechanistic basis of this process. Myomaker belongs to a small family of related membrane proteins that are expressed in other cell types, suggesting a general mechanism for cell-cell fusion. The goals of this project are to define the precise molecular mechanism whereby Myomaker drives myoblast fusion and to identify additional components of the process through which Myomaker exerts its fusogenic activity. The insights gleaned from these studies will shed light not only on the fundamental mechanisms of intercellular fusion but will also have important implications for understanding muscle disease and for the potential development of new therapeutic strategies for restoration of function to diseased muscle.