Unravelling the Impact of Adipokines on Muscle Satellite Cell Regulation

揭示脂肪因子对肌肉卫星细胞调节的影响

• 批准号: RGPIN-2018-06324
• 负责人: Hawke, Thomas
• 金额: $ 4.01万
• 依托单位: McMaster University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761971
• 关键词: Unravelling; Impact; Adipokines; Muscle; Satellite

The role of adipocyte-secreted signaling molecules (adipokines) in altering skeletal muscle metabolism has garnered much interest in the past twenty years with the global rise in obesity. However, the impact of adipokines on muscle's Satellite Cell (MSC) population, the stem cells of muscle, is virtually unknown. Consistent with our long-term objective to uncover novel regulators of MSCs, we propose to investigate the effects of selected adipokines on MSC function and determine if manipulating adipokine levels will impact the ability of mouse skeletal muscle to grow or repair from injury. We hypothesize that altering these adipokine levels will negatively impact MSC function and ultimately attenuate skeletal muscle growth and regeneration.To address this hypothesis, our 5 year plan will seek to achieve the following goals: Goal #1: Define the impact of specific adipokines on MSC functionIn vitro studies will be used to investigate the effects of manipulating selected adipokine levels (alone and in combination) on primary MSCs. Initial experiments will test: Lipocalin-2, Retinol binding protein-4, Vaspin and Resistin. Primary MSC cultures and isolated single muscle fibres will be used to assess the capacity for MSC activation, proliferation and differentiation in response to varying adipokine expression. We will also assess the ability of selected adipokines to induce epigenetic changes on MSC. Goal #2: Understand the effects of altered adipokine levels on skeletal muscle growth ">future pharmaceutical and medical research into improving muscle quality in conditions where adipokine levels may be dysregulated (obesity, lipodystrophy). Given the known relationship between skeletal muscle health and longevity, these foundational studies are of immediate and lasting importance. This research will also provide the platform for the training of >10 graduate and undergraduate students in the areas of physiology, cellular/molecular biology and biochemistry; high-demand areas within industry, academia, patent law and education.

在过去的二十年里，随着全球肥胖率的上升，脂肪细胞分泌的信号分子(脂肪因子)在改变骨骼肌代谢中的作用引起了人们的极大兴趣。然而，脂肪因子对肌肉的卫星细胞(MSC)群体--肌肉干细胞--的影响几乎是未知的。与我们发现MSCs新调控因子的长期目标一致，我们建议研究部分脂肪因子对MSC功能的影响，并确定操纵脂肪因子水平是否会影响小鼠骨骼肌生长或修复损伤的能力。我们假设，改变这些脂肪因子水平将对MSC的功能产生负面影响，并最终削弱骨骼肌的生长和再生。为了解决这一假设，我们的五年计划将寻求实现以下目标：目标1：确定特定脂肪因子对MSC功能的影响体外研究将使用操纵选定的脂肪因子水平(单独和联合)对原代MSCs的影响。初步实验将测试：Lipocalin-2、视黄醇结合蛋白-4、Vaspin和抵抗素。原代培养的MSC和分离的单个肌肉纤维将用于评估MSC的激活、增殖和分化能力，以响应不同的脂肪因子表达。我们还将评估选定的脂肪因子诱导MSC表观遗传学变化的能力。目标2：了解脂肪因子水平改变对骨骼肌生长的影响“&gt；未来的制药和医学研究旨在改善脂肪因子水平可能失调(肥胖、脂肪营养不良)的条件下的肌肉质量。鉴于骨骼肌健康和寿命之间的已知关系，这些基础研究具有直接和持久的重要性。这项研究还将为10名研究生和本科生在生理学、细胞/分子生物学和生物化学领域的培训提供平台；这些领域是工业、学术界、专利法和教育领域的高需求领域。