Plasminogen activator inhibitor-1-mediated regulation of skeletal muscle regeneration

骨骼肌是一种特殊的器官，它是一种生理运动，赋予动物（包括人类）执行各种体力任务的能力。然而，进行这些活动会导致骨骼肌损伤：要求更高的任务会导致更大的损伤。因此，骨骼肌需要不断的修复来维持它的体能。基础肌肉生物学/生理学的一个重要方面是组织如何对损伤作出反应以诱导修复过程，然而，调节骨骼肌损伤后修复的因素是复杂的，我们目前的理解是有限的。在经历肌肉损伤后，包括炎症细胞和骨骼肌干细胞（称为卫星细胞）在内的大量细胞反应会清理和修复受损组织。这种反应受到一种称为纤溶酶原激活物抑制剂(PAI)-1的蛋白质激素的严重影响。高浓度的PAI-1阻断了组织激活细胞反应的能力，因此损害了组织重塑和修复。确定PAI-1如何运作，它在控制细胞活动和整体修复过程中所起的作用将有助于更好地了解骨骼肌再生过程。提出的实验重点是研究PAI-1如何控制选择的下游蛋白质，这些蛋白质允许炎症和卫星细胞在肌肉损伤后发挥作用，以及如何通过评估与控制骨骼肌质量相关的特定激素来调节PAI-1本身。我假设：1)在巨噬细胞和激活的卫星细胞中观察到损伤性抗阻运动后巨噬细胞和卫星细胞中PAI-1活性降低、蛋白酶活性增加和细胞内信号传导增加的协调模式；2)已知限制肌肉生长的激素会激活PAI-1的表达并降低PAI-1下游蛋白酶的表达/活性。来自基因敲除小鼠的组织和细胞将使用各种尖端技术和方法进行研究。在动物实验中证明的结果将在一项涉及人类参与者的研究中得到复制和评估，他们将进行不同的运动模式，以刺激PAI-1系统。这项研究将回答关于内分泌系统和骨骼肌之间先前未被探索的相互作用的基本问题，将为未来的研究确定有前途的领域，并启动有影响力的知识转移机会。

Skeletal muscle is an exceptional organ that is the physiological motor that gives animals (including humans) the ability to perform a wide range of physical tasks. However, performing these activities can result in skeletal muscle damage: more demanding tasks will lead to a greater amount of damage. As a result, skeletal muscle requires constant repair to maintain its physical capacity. An important aspect of basic muscle biology/physiology is how the tissue responds to damage to induce repair processes, however, the factors regulating skeletal muscle repair following injury are complex and our current understanding is limited. After experiencing muscle damage, a large cellular response, including inflammatory cells and skeletal muscle stem cells (called satellite cells), cleans up and repairs the damaged tissue. This response is heavily influenced by a protein hormone known as plasminogen activator inhibitor (PAI)-1. High concentrations of PAI-1 block the ability of tissues to activate the cellular response, therefore compromising tissue remodeling and repair. Determining how PAI-1 operates, the role it plays in controlling cellular activity and the overall repair process will contribute to greater understanding of the process of skeletal muscle regeneration. The proposed experiments focus on investigating how PAI-1 controls selected downstream proteins that allow inflammatory and satellite cells to function following muscle damage, as well as examining how PAI-1 itself is regulated through assessment of particular hormones related to the control skeletal muscle mass. I hypothesize that: 1) a coordinated pattern of reduced PAI-1 activity, increased protease activity, and increased intracellular signalling in macrophages and satellite cells following damaging resistance exercise will be observed in macrophages and activated satellite cells; and 2) hormones known to limit muscle growth will activate PAI-1 expression and reduce expression/activity of PAI-1’s downstream proteases. Tissues and cells from genetic knockout mice will be studied using a variety of cutting edge techniques and methods. Results demonstrated in the animal experiments will then be replicated and evaluated in a study involving human participants who will perform different exercise modes in order to stimulate the PAI-1 system. This research will answer fundamental questions about previously unexplored interactions between the endocrine system and skeletal muscle, will identify promising areas for future research, and initiate impactful knowledge transfer opportunities.