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

纤溶酶原激活剂抑制剂-1介导的骨骼肌再生调节

• 批准号: RGPIN-2016-05073
• 负责人: Krause, Matthew
• 金额: $ 1.82万
• 依托单位: University of Windsor
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=708615
• 关键词: Plasminogen; activator; inhibitor; mediated; regulation

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.

骨骼肌是一种特殊的器官，它是一种生理运动，使动物（包括人类）能够执行各种身体任务。然而，执行这些活动可能会导致骨骼肌损伤：要求更高的任务会导致更大的损伤。 因此，骨骼肌需要不断修复以维持其身体能力。 基础肌肉生物学/生理学的一个重要方面是组织如何响应损伤以诱导修复过程，然而，损伤后调节骨骼肌修复的因素很复杂，我们目前的理解是有限的。 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并修复受损组织。 这种反应很大程度上受到称为纤溶酶原激活剂抑制剂 (PAI)-1 的蛋白质激素的影响。 高浓度的 PAI-1 会阻碍组织激活细胞反应的能力，从而损害组织重塑和修复。 确定 PAI-1 的运作方式、它在控制细胞活动中的作用以及整体修复过程将有助于更好地了解骨骼肌再生过程。 拟议的实验重点是研究 PAI-1 如何控制选定的下游蛋白质，使炎症细胞和卫星细胞在肌肉损伤后发挥作用，以及检查 PAI-1 本身如何通过评估与控制骨骼肌质量相关的特定激素进行调节。我假设：1）在破坏性抵抗运动后，将在巨噬细胞和活化的卫星细胞中观察到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 表达并降低 PAI-1 下游蛋白酶的表达/活性。将使用各种尖端技术和方法对基因敲除小鼠的组织和细胞进行研究。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，人类参与者将执行不同的运动模式以刺激 PAI-1 系统。 这项研究将回答有关内分泌系统和骨骼肌之间先前未探索的相互作用的基本问题，将为未来研究确定有希望的领域，并启动有影响力的知识转移机会。