Myokine function of MG53 in muscle injury-repair and regeneration

总结 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， 肌纤维膜、动员卫星细胞替代丢失的肌纤维和控制纤维化 重塑以维持肌肉完整性。在肌营养不良症中，受损的肌膜完整性或 膜修复触发了肌肉退化的级联反应，导致进行性的严重发病率， 最终死亡。开发治疗方法以改善肌膜完整性，同时促进 损伤肌纤维的再生仍然是肌肉生理学研究中的主要挑战。这个项目 建立在TRIM家族蛋白质成员MG 53作为细胞必需成分的发现的基础上 膜修复机械MG 53在囊泡运输中起作用，并促进细胞内的成核。 囊泡到膜破裂的位点以形成修复补丁。天然MG 53存在于血液循环中， 其水平与肌肉的损伤或分泌活动直接相关。施用重组人 MG 53（rhMG 53）蛋白保护肌纤维和干细胞免受损伤，并减少肌肉纤维化， mdx小鼠模型。我们在过去几年中对MG 53的研究已经建立了一个潜在的三功能 MG 53在肌肉损伤-再生中的作用，作为修复急性肌膜损伤的促进剂， 在肌肉损伤的早期阶段激活卫星细胞，并通过控制纤维化的调节剂 成纤维细胞分化与慢性肌肉损伤有关。我们设想， MG 53的治疗将具有优于目前用于治疗肌营养不良症的范例的优势。在目标1中，我们 确定将新鉴定的MG 53的肌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;定义MG 53调节 慢性肌肉损伤期间的纤维化;并测试非侵入性干预是否可以调节循环MG 53 肌肉损伤再生的水平。如果循环MG 53在卫星细胞活化中起作用，我们预测 在没有肌肉损伤的情况下释放MG 53的缺血预处理，或从肌肉中诱导MG 53的分泌， 转基因小鼠模型，将有效地激活卫星细胞和肌肉再生损伤后。在Aim中 2、我们将评估持续升高循环中MG 53以保存肌肉的安全性和有效性 完整性/卫星细胞活化/纤维化控制。履行 该项目的研究将推进MG 53在肌肉损伤修复和再生中的生物学，并奠定 这为我们靶向MG 53功能治疗肌营养不良症的翻译方法奠定了基础。

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.