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: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=615482
• 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，是赋予动物（包括人类）执行各种体力任务的能力的生理运动。然而，进行这些活动可能会导致骨骼肌损伤：更苛刻的任务将导致更大的损伤。因此，骨骼肌需要不断修复以维持其体能。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是复杂的，我们目前的理解是有限的。在经历肌肉损伤后，一个大的细胞反应，包括炎症细胞和骨骼肌干细胞（称为卫星细胞），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（派）-1的蛋白质激素的严重影响。高浓度的派-1阻断组织激活细胞反应的能力，因此损害组织重塑和修复。确定派-1如何运作，它在控制细胞活性和整体修复过程中发挥的作用将有助于更好地了解骨骼肌再生的过程。拟议的实验重点研究派-1如何控制选定的下游蛋白质，使炎症和卫星细胞在肌肉损伤后发挥作用，以及研究派-1本身如何通过评估与控制骨骼肌质量相关的特定激素来调节。我假设：1）在巨噬细胞和活化的卫星细胞中将观察到破坏性阻力运动后巨噬细胞和卫星细胞中派-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;和2）已知限制肌肉生长的激素将活化派-1表达并降低派-1下游蛋白酶的表达/活性。将使用各种尖端技术和方法研究基因敲除小鼠的组织和细胞。然后，在动物实验中证明的结果将在涉及人类参与者的研究中进行复制和评估，这些参与者将执行不同的运动模式以刺激派-1系统。这项研究将回答有关内分泌系统和骨骼肌之间以前未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。