Mechanisms of resealing and rebuilding in muscle repair

肌肉修复中的重新封闭和重建机制

• 批准号: 10734597
• 负责人: ALEXIS R. DEMONBREUN
• 金额: $ 40万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734597
• 关键词: Actins; Acute; Annexin A6; Annexins; Area; Cells; Chronic Disease; Cytoplasm; DNA Sequence Alteration; DYSF gene; Defect; Dependence; Disease; Dominant-Negative Mutation; Event; Extracellular Matrix; F-Actin; Family member; Genetic; Genetic Diseases; Health; Homologous Gene; Hour; Injury; Membrane; Molecular; Muscle; Muscle Contraction; Muscle function; Muscular Atrophy; Muscular Dystrophies; Myoblasts; Outcome; Pharmacology; Phase; Polymers; Process; Proliferating; Proteins; Research; Resolution; Role; Sarcolemma; Sarcomeres; Shoulder; Site; Therapeutic; Time; Trauma; Visualization; Work; cell motility; cell type; extracellular; improved; injured; injury and repair; migration; novel; polymerization; progenitor; programs; recruit; repaired; seal; tool

Muscle repair is essential to maintain normal muscle function. Muscle injury, whether due to trauma or overuse, is associated with a loss of muscle membrane integrity. Resealing the disrupted sarcolemma is a critical step needed for muscle repair. Subtypes of muscular dystrophy arise from genetic mutations that weaken the sarcolemma, rendering it prone to disruption and requiring robust repair mechanisms. Other subtypes of muscular dystrophy arise from genetically-driven deficits in repair proteins, and these genetic disorders have illustrated proteins and mechanisms that contribute to membrane stability and membrane repair. Studies of injured muscle and dystrophic muscle have uncovered phases of muscle repair, an immediate resealing phase followed by a rebuilding phase. Sarcolemmal resealing occurs through the formation of a cap at the site of muscle membrane disruption. We and others have shown that this cap is enriched for annexin proteins, especially annexin A6, a modifier of muscular dystrophy. Dominant negative annexin A6 disrupts the formation of the repair cap, through its effects on annexin assembly, leading to excessive membrane leak and ineffective repair. The repair cap is supported by a ring of “shoulder” proteins that serve to reinforce the resealing process, and these proteins include dysferlin, MG53, and EHD proteins. Within the muscle cytoplasm immediately abutting sarcolemmal disruption is an active area that is enriched for actin and the dysferlin related protein, Fer1L5. Moreover, actin polymerization is required for normal resealing. Recent work highlighted the role of muscle rebuilding, which follows sarcolemma resealing and includes sarcomere assembly. Through this research program, we previously demonstrated the role of ferlin proteins and annexins in sarcolemmal resealing by optimizing high-resolution real-time visualization. We also developed novel genetic tools to elucidate the interaction of these proteins in membrane events. We now propose to investigate the role of resealing proteins in their interaction with the actin-rich region in Aim 1. In Aim 2, we will examine the molecular and temporal overlap of resealing and rebuilding during muscle repair. In Aim 3, we will use biologically active decellularized matrices to define and probe the role of extracellular annexins in regulating cellular contributions to muscle repair in health and disease. The outcomes of this work will discover new protein-cellular interactions to guide the pharmacology of promoting muscle repair.

肌肉修复是维持正常肌肉功能所必需的。肌肉损伤，不管是外伤还是

项目成果

Ferlin proteins in myoblast fusion and muscle growth.

• DOI: 10.1016/b978-0-12-385940-2.00008-5
• 发表时间: 2011
• 期刊: CURRENT TOPICS IN DEVELOPMENTAL BIOLOGY
• 作者: Posey, Avery D., Jr.;Demonbreun, Alexis;McNally, Elizabeth M.
• 通讯作者: McNally, Elizabeth M.

A KCNE1 missense variant (V47I) causing exercise-induced long QT syndrome (Romano Ward).

KCNE1 错义变异 (V47I) 导致运动诱发的长 QT 综合征 (Romano Ward)。

• DOI: 10.1016/j.ijcard.2011.08.022
• 发表时间: 2012
• 期刊: International journal of cardiology
• 影响因子: 3.5
• 作者: Ryan,JohnJ;Kalscheur,Matthew;Dellefave,Lisa;McNally,Elizabeth;Archer,StephenL
• 通讯作者: Archer,StephenL