MG53 function in muscle aging

MG53在肌肉衰老中的作用

基本信息

批准号：
10442137
负责人：
Jianjie Ma
金额：
$ 64.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442137
关键词：
Adverse effects Age Age-Months Aging Animal Model Animals Anti-Inflammatory Agents Area Attenuated Benefits and Risks Biochemistry Biology Blood Circulation Cell physiology Cellular biology Chronic Clustered Regularly Interspaced Short Palindromic Repeats Data Dose Doxycycline Elderly Exercise Foundations Functional disorder Genes Goals Human Impairment Individual Inflammation Injury Knock-in Mouse Lead Longevity Manuscripts Measurable Mediating Molecular Molecular Biology Mus Muscle Muscle Weakness Muscle function Muscle satellite cell Muscular Atrophy Natural regeneration Nature Organ Outcome Study Oxidative Stress Pathology Persons Physical Function Physical activity Pilot Projects Play Post-Translational Protein Processing Protein Family Proteins Proteomics Publishing Recombinants Regenerative Medicine Regenerative capacity Rejuvenation Research Research Design Role Sarcolemma Sentinel Serum Skeletal Muscle Skeletal Muscle Satellite Cells Stains Stress TRIM Gene Testing Therapeutic Tissues Transgenic Mice Translating Wild Type Mouse age related age-related muscle loss aged exosome genome editing improved in vivo injury and repair insight live cell imaging member microvesicles mouse model muscle aging muscle regeneration muscle transplantation muscular system preservation regeneration following injury regenerative tissue repair function repaired response satellite cell tissue injury tissue regeneration tissue repair tool wound healing

项目摘要

PROJECT SUMMARY Elderly persons are susceptible to injury with compromised regenerative capacity of the skeletal muscle, leading to gradual muscle weakness and loss of physical activity. Impaired myogenic satellite cell function is associated with muscle aging. While it is known that exercise has many beneficial effects on aging and can improve satellite cell function, searching for the putative myogenic factors that facilitate exercise-mediated improvement of muscle function presents an attractive area for geriatric research. We know that exercise induces secretion of MG53 from skeletal muscle into circulation, which serves as a myokine to protect multiple tissues from injuries. However, exercise-induced MG53 release is severely attenuated in aging. Chronic oxidative stress associated with aging leads to MG53 aggregation that compromises MG53’s function in tissue repair and regeneration. We hypothesize rejuvenating MG53’s myokine function will have benefits to aging. We have produced a transgenic mouse model with sustained elevation of MG53 in the bloodstream, and found that these mice display remarkable muscle regeneration following injury. We have data to show that treatment with recombinant human MG53 (rhMG53) protein promotes proliferation and protects against stress-induced injury to muscle satellite cells. Therefore, we propose to test if improvement of muscle satellite cell function by MG53 can provide long-term benefits to muscle aging. Chronic oxidative stress and inflammation associated with aging may cause tissue injury and consequently the elevation of MG53 in circulation. We will use a combination of live cell imaging, proteomic, and CRISPR-gene editing tools to test if post-translational modification of MG53 in the serum can be a contributing factor for MG53’s compromised tissue repair function during aging. Outcomes of the studies in this project can lay the foundation and pave the way for our long-term goal of translating the basic findings of the benefits of MG53 into therapeutic treatments of age-related muscle dysfunctions.

项目摘要老年人容易受到骨骼肌再生能力受损的伤害，领先评分肌肉无力和体育锻炼的丧失。肌源性卫星细胞功能受损随着肌肉衰老。虽然众所周知，运动对衰老有许多有益的影响，并且可以改善卫星细胞功能，寻找促进运动介导的肌肉改善的假定肌原因素功能为老年研究提供了一个有吸引力的领域。我们知道运动会诱导MG53的分泌从骨骼肌到循环，作为肌动物，可以多次保护肌动物。然而，运动引起的MG53释放在衰老中严重减弱。与衰老相关的慢性氧化应激导致MG53聚集，从而损害了MG53在组织修复和再生中的功能。我们假设恢复MG53的肌动物功能将对衰老带来好处。我们已经产生了一个转基因小鼠模型血液中MG53的持续升高，发现这些鼠标表现出显着的肌肉受伤后再生。我们有数据表明，重组人MG53（RHMG53）治疗蛋白质促进增殖并防止应激引起的肌肉卫星细胞损伤。因此，我们提议测试MG53改善肌肉卫星细胞功能是否可以为肌肉提供长期益处老化。与衰老有关的慢性氧化应激和炎症可能会导致组织损伤，并且因此，循环中MG53的升高。我们将结合活细胞成像，蛋白质组学和 CRISPR-GENE编辑工具以测试血清中MG53的翻译后修改是否可以有效 MG53在衰老过程中受损的组织修复功能的因子。该项目的研究结果可以为我们的长期目标奠定基础，并为翻译基本发现的好处铺平了道路 MG53进入与年龄有关的肌肉功能障碍的治疗治疗。