Myokine function of MG53 in muscle injury-repair and regeneration

MG53在肌肉损伤修复和再生中的肌因子功能

• 批准号: 9924247
• 负责人: Jianjie Ma
• 金额: $ 35.27万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924247
• 关键词: Acute; Address; Animal Model; Area; Biological; Biology; Biomedical Research; Blood Circulation; Cell membrane; Cell physiology; Cellular Structures; Cessation of life; Chronic; Chronic Phase; Clinical Research; Data; Development; Fibroblasts; Fibrosis; Foundations; Goals; Human; Immune response; Injury; Intervention; Ischemia; Ischemic Preconditioning; Learning; Link; Longevity; Maintenance; Membrane; Morbidity - disease rate; Multicellular Process; Mus; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Muscular Dystrophies; Myofibroblast; Myopathy; Natural regeneration; Pathway interactions; Phase; Physiological; Play; Process; Proliferating; Property; Protein Family; Proteins; Reagent; Recombinants; Regenerative Medicine; Regulation; Research; Role; Safety; Sarcolemma; Signal Transduction; Site; Skeletal Muscle; Skeletal muscle injury; Stress; TRIM Family; Testing; Therapeutic; Transgenic Mice; Translating; Vesicle; Wild Type Mouse; cell injury; cell regeneration; design; experimental study; extracellular; fiber cell; gene repair; improved; injured; injury and repair; intravenous administration; mdx mouse; member; mortality; mouse model; muscle degeneration; muscle physiology; muscle regeneration; novel; novel therapeutic intervention; preconditioning; preservation; prevent; regenerative; repaired; response; satellite cell; stem cells; tissue regeneration; trafficking; translational approach

SUMMARY Skeletal muscle injury-repair and regeneration is a multi-cellular process that involves repair of acute injury to the sarcolemma, mobilization of satellite cells to replace the lost-muscle fibers, and control of fibrotic remodeling for maintenance of muscle integrity. In muscular dystrophy, compromised sarcolemma integrity or membrane repair triggers the cascade of muscle degeneration that incurs progressive, severe morbidity and ultimately mortality. Developing therapeutic approaches to improve sarcolemma integrity while facilitating regeneration of injured muscle fibers remain a major challenge in muscle physiology research. This project builds on the discovery of MG53, a member of the TRIM-family protein, as an essential component of the cell membrane repair machinery. MG53 functions in vesicle trafficking and facilitates the nucleation of intracellular vesicles to sites of membrane disruption for repair patch formation. Native MG53 is present in blood circulation, at levels directly correlating with injury or secretory activity of the muscle. Administration of recombinant human MG53 (rhMG53) protein protects muscle fibers and stem cells from injury, and reduces muscle fibrosis in the mdx mouse model. Our research with MG53 over the past few years has established a potential tri-functional role for MG53 in muscle injury-regeneration, as a facilitator to repair acute sarcolemma injury, a contributor to activate satellite cells during the early phase of muscle injury, and a modulator of fibrosis by controlling fibroblast differentiation associated with chronic muscle injury. We envision that targeting the tri-functional role of MG53 will have advantage over the current paradigms for treating muscular dystrophy. In Aim 1, we will determine the pathways that transduce the newly identified myokine function of MG53 into activation of satellite cells in response to acute muscle injury; define the mechanisms that underlie MG53’s function in regulating fibrosis during chronic muscle injury; and test if non-invasive interventions can modulate circulating MG53 levels toward muscle injury-regeneration. If circulating MG53 plays a role in satellite cell activation, we predict that ischemia-preconditioning that releases MG53 without muscle injury, or inducible secretion of MG53 from a transgenic mouse model, will effectively activate satellite cells and muscle regeneration following injury. In Aim 2, we will evaluate the safety and efficacy for sustained elevation of MG53 in circulation to preserve muscle integrity/satellite cell activation/fibrosis control in animal models of muscular dystrophy. Fulfillment of the studies in this project will advance the biology of MG53 in muscle injury-repair and regeneration, and lay the foundation for our translational approach for targeting MG53 function for treatment of muscular dystrophy.

概括 骨骼肌损伤修复和再生是一个多细胞过程，涉及修复急性损伤 肌膜，动员卫星细胞以取代损失的肌肉纤维，并控制纤维化 改造以维持肌肉完整性。在肌肉营养不良中，肌膜完整性受损或 膜修复会触发一系列肌肉变性，会导致渐进性，严重的发病率和 最终死亡率。开发治疗方法以改善肌膜完整性，同时促进 受伤的肌肉纤维的再生仍然是肌肉生理研究中的主要挑战。这个项目 建立在发现蛋白质的成员MG53的基础上，作为细胞的重要组成部分 膜维修机械。 MG53在囊泡运输中起作用并促进细胞内的成核 膜破坏部位的工厂，以形成修复斑块的形成。本地MG53存在于血液循环中， 在与肌肉的损伤或分泌活动直接相关的水平上。重组人的管理 MG53（RHMG53）蛋白保护肌肉纤维和干细胞免受损伤，并减少肌肉纤维化 MDX鼠标模型。在过去的几年中，我们对MG53的研究建立了潜在的三功能 MG53在肌肉损伤再生中的作用，作为修复急性肌体损伤的促进者 在肌肉损伤的早期阶段激活卫星细胞，并通过控制 与慢性肌肉损伤相关的成纤维细胞分化。我们设想针对三功能角色 MG53的优势将比当前治疗肌肉营养不良的范例具有优势。在AIM 1中，我们将 确定将新近鉴定的MG53肌动物功能转化为卫星激活的途径 响应急性肌肉损伤的细胞；定义MG53在调节中的功能的机制 慢性肌肉损伤期间的纤维化；并测试非侵入性干预措施是否可以调节循环MG53 肌肉损伤再生的水平。如果循环MG53在卫星细胞激活中起作用，我们预测 局部局部释放MG53而无需肌肉损伤，或从A中诱导的MG53分泌 转基因小鼠模型将有效地激活卫星细胞和受伤后的肌肉再生。目标 2，我们将评估循环中MG53持续升高以保持肌肉的安全性和效率 肌肉营养不良的动物模型中的完整性/卫星细胞激活/纤维化控制。实现 该项目的研究将推进MG53在肌肉损伤修复和再生中的生物学，并放置 我们针对MG53功能治疗肌营养不良症的转化方法的基础。