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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

基本信息

批准号：
10268967
负责人：
Renzhi Han
金额：
$ 34.21万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10268967
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 Regenerative capacity 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 efficacy evaluation 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 regeneration following injury regenerative repaired response satellite cell stem cells tissue regeneration trafficking translational approach

项目摘要

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.

摘要骨骼肌损伤-修复和再生是一个多细胞过程，涉及急性损伤的修复肌膜，动员卫星细胞以替代丢失的肌肉纤维，以及控制纤维化重塑以保持肌肉的完整性。在肌营养不良症中，肌膜完整性或膜修复触发肌肉退行性变的级联反应，导致进行性、严重的发病率和最终是死亡。开发治疗方法以改善肌膜完整性，同时促进损伤肌肉纤维的再生仍然是肌肉生理学研究中的一大挑战。这个项目建立在发现MG53的基础上，MG53是TRIM家族蛋白的成员，是细胞的重要组成部分膜修补机械。MG53在囊泡运输中的作用并促进细胞内的成核小泡到膜破裂的部位以修复补丁的形成。天然的MG53存在于血液循环中，与肌肉损伤或分泌活动直接相关的水平。重组人的给药 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小鼠模型。我们在过去几年对MG53的研究已经建立了一个潜在的三功能 MG53在肌肉损伤-再生中的作用，作为修复急性肌膜损伤的促进器，贡献于在肌肉损伤的早期阶段激活卫星细胞，并通过控制成纤维细胞分化与慢性肌肉损伤相关。我们设想，以三大职能角色为目标与目前治疗肌营养不良症的范例相比，MG53的治疗方案将具有优势。在目标1中，我们将确定将新发现的MG53肌动因子功能转化为卫星激活的途径细胞对急性肌肉损伤的反应；确定MG53的S调节功能的机制慢性肌肉损伤时的纤维化；以及测试非侵入性干预是否可以调节循环MG53 肌肉损伤-再生的水平。如果循环中的MG53在卫星细胞激活中起作用，我们预测在不损伤肌肉的情况下释放MG53的缺血预适应，或从转基因小鼠模型，将有效激活损伤后的卫星细胞和肌肉再生。在AIM 2、我们将评估持续升高循环中MG53以保存肌肉的安全性和有效性肌营养不良动物模型的完整性/卫星细胞激活/纤维化控制。履行本项目的研究将促进MG53在肌肉损伤修复和再生方面的生物学研究，并为为我们针对MG53功能治疗肌营养不良症的翻译方法奠定基础。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MG53 suppresses tumor progression and stress granule formation by modulating G3BP2 activity in non-small cell lung cancer.

DOI：
10.1186/s12943-021-01418-3
发表时间：
2021-09-14
期刊：
Molecular cancer
影响因子：
37.3
作者：
Li H;Lin PH;Gupta P;Li X;Zhao SL;Zhou X;Li Z;Wei S;Xu L;Han R;Lu J;Tan T;Yang DH;Chen ZS;Pawlik TM;Merritt RE;Ma J
通讯作者：
Ma J

BVES is a novel interactor of ANO5 and regulates myoblast differentiation.

BVES 是 ANO5 的一种新型相互作用因子，可调节成肌细胞分化。

DOI：
10.1186/s13578-021-00735-w
发表时间：
2021-12-28
期刊：
Cell & bioscience
影响因子：
7.5
作者：
Li H;Xu L;Gao Y;Zuo Y;Yang Z;Zhao L;Chen Z;Guo S;Han R
通讯作者：
Han R

Cardiac differentiation of cardiosphere-derived cells in scaffolds mimicking morphology of the cardiac extracellular matrix.

DOI：
10.1016/j.actbio.2014.04.018
发表时间：
2014-08
期刊：
Acta biomaterialia
影响因子：
9.7
作者：
Xu Y;Patnaik S;Guo X;Li Z;Lo W;Butler R;Claude A;Liu Z;Zhang G;Liao J;Anderson PM;Guan J
通讯作者：
Guan J

Multi-Cellular Functions of MG53 in Muscle Calcium Signaling and Regeneration.