MG53 function in muscle aging

项目总结 老年人容易受伤，骨骼肌再生能力受损，导致 到逐渐的肌肉无力和体力活动的丧失。肌源性卫星细胞功能受损与 伴随着肌肉老化。虽然众所周知，锻炼对衰老有许多有益的影响，而且可以改善卫星 细胞功能，寻找促进运动介导的肌肉改善的可能的肌肉生成因子 功能是老年学研究的一个有吸引力的领域。我们知道运动可以诱导MG53的分泌 从骨骼肌进入循环，这是一种肌动因子，保护多种组织免受伤害。然而， 运动诱导的MG53释放在衰老过程中严重减弱。与衰老相关的慢性氧化应激 导致MG53聚集，影响MG53的S在组织修复和再生中的功能。我们假设 恢复MG53的S肌动因子功能将有益于衰老。我们已经培育出一种转基因小鼠模型 血液中MG53持续升高，并发现这些小鼠表现出显著的肌肉 受伤后的再生。我们有数据表明，用重组人MG53(RhMG53)治疗 蛋白质促进增殖，保护肌肉卫星细胞免受应激损伤。因此，我们 建议测试MG53改善肌肉卫星细胞功能是否能为肌肉提供长期好处 衰老。与衰老相关的慢性氧化应激和炎症可能会导致组织损伤和 因此，MG53在流通中的升高。我们将使用活细胞成像、蛋白质组学和 CRISPR-基因编辑工具，用于测试血清中MG53的翻译后修饰是否有助于 MG53的致病因子S在衰老过程中损害了组织修复功能。该项目的研究成果可以 为我们的长期目标奠定基础和铺平道路，我们的长期目标是将 MG53用于治疗与年龄相关的肌肉功能障碍。

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.