Anti-inflammatory mechanisms of exercise during human growth

人体生长过程中运动的抗炎机制

• 批准号: RGPIN-2014-05398
• 负责人: Timmons, Brian
• 金额: $ 2.19万
• 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: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=588390
• 关键词: Anti; inflammatory; mechanisms; exercise; during

INTRODUCTION: Exercise is a potent stimulus to the human immune system and emerging evidence points to several anti-inflammatory properties of exercise. Studying these properties is important because when inflammation becomes dysfunctional multiple organs are negatively affected. One major consequence of chronic inflammation is impaired development of skeletal muscle. However, inflammation is not always bad and often is necessary to facilitate tissue adaptation in response to stress or injury, including muscle regeneration. This apparent paradox creates an exciting paradigm to study exercise as a unique model that appears to have both anti- and pro-inflammatory effects. Over the next 5 years, I plan to understand this balancing act of exercise, inflammation, and skeletal muscle. OBJECTIVES: My research program has the long-term goal of understanding the effects of exercise on the immune system during human growth. To achieve this goal, I will address short-term objectives with an integrative, multi-disciplined approach with appropriate collaboration when necessary. Short-term objectives for the next 5 years: 1. To characterize the time-course of the inflammatory response to muscle damage; 2. To clarify the effects of exercise on components of IL-6 signalling; 3. To characterize the cytokine signature of different types of exercise; 4. To understand the anti-inflammatory effects of exercise in the context of muscle development. METHODS Objective 1: It is not known if the inflammatory response to muscle damage is influence by growth. Thus, boys and men will perform exercise designed to produce muscle damage. I will collect blood samples at various time points after the exercise to evaluate the time-course response of specific immune cells. I will not only quantify these cells, but also measure their function, including their ability to produce mediators such as cytokines and growth factors that are thought be involved in muscle repair and regeneration (e.g., IGF-1 and IL-6). Objective 2: Much of the research on the anti-inflammatory effects of exercise has focused on the role of IL-6, which has both pro- and anti-inflammatory properties. However, virtually nothing has been done to characterize the components of IL-6 signalling, which is essential to understand since the method of signalling (classical vs. trans-signalling) is critical to whether IL-6 exerts pro- or anti-inflammatory effects. Boys and men will complete a specific episode of exercise performed at the same relative intensity and I will carefully measure IL-6, soluble IL-6 receptor, and soluble gp130 – all of which are the main components of IL-6 signalling. Objective 3: Because cytokines function in a network, it is not sufficient to focus only on one or two of these proteins at a time. It is also unknown if different types of exercise can generate the same kind of cytokine responses, especially in children. Thus, I will characterize the cytokine signature of different types of exercise by using multi-array cytokine assays to assess multiple cytokines simultaneously and determine whether the balance in pro- or anti-inflammatory cytokines is different between boys and men. Objective 4: Finally, I will perform in vitro experiments to understand the anti-inflammatory effects of exercise in the context of muscle development. Using serum collected as part of Objective 3, I will co-incubate exercise serum with C2C12 myoblasts, with and without the inflammatory cytokine, TNF-a, present. Our initial findings show that exercise serum can inhibit the negative effects of TNF-a on muscle. We want to extend these exciting findings and determine what other aspects of muscle development are affected and what pathways are involved.

导语：运动是对人体免疫系统的一种强有力的刺激，越来越多的证据表明运动具有几种抗炎特性。研究这些特性很重要，因为当炎症变得功能失调时，多个器官会受到负面影响。慢性炎症的一个主要后果是骨骼肌发育受损。然而，炎症并不总是有害的，而且往往是促进组织适应压力或损伤(包括肌肉再生)所必需的。这一明显的悖论创造了一个令人兴奋的范式，将运动作为一种似乎同时具有抗炎和促炎作用的独特模型来研究。在接下来的5年里，我计划了解运动、炎症和骨骼肌之间的平衡。 目的：我的研究计划有一个长期目标，即了解运动对人类发育过程中免疫系统的影响。为了实现这一目标，我将采取综合的、多学科的方法，并在必要时进行适当的合作，以解决短期目标。未来5年的短期目标： 1.表征肌肉损伤后炎症反应的时程； 2.阐明运动对IL-6信号成分的影响； 3.表征不同类型运动的细胞因子特征； 4.从肌肉发育的角度理解运动的抗炎作用。 方法 目的1：目前尚不清楚肌肉损伤后的炎症反应是否受生长的影响。因此，男孩和男人将进行旨在产生肌肉损伤的运动。我会在运动后的不同时间点采集血液样本，以评估特定免疫细胞的时程反应。我不仅将量化这些细胞，还将测量它们的功能，包括它们产生细胞因子和生长因子等被认为参与肌肉修复和再生的介质的能力(例如，IGF-1和IL-6)。 目的：运动抗炎作用的研究大多集中在IL-6的作用上，IL-6既有促炎作用，又有抗炎作用。然而，几乎没有人研究IL-6信号的组成成分，这是理解IL-6信号的关键，因为信号的方法(经典信号与反式信号)是IL-6发挥促炎或抗炎作用的关键。男孩和男人都会在相同的相对强度下完成一段特定的运动，我会仔细测量IL-6、可溶性IL-6受体和可溶性gp130--所有这些都是IL-6信号的主要成分。 目标3：由于细胞因子在一个网络中发挥作用，一次只关注其中的一到两个蛋白质是不够的。不同类型的运动是否能产生相同类型的细胞因子反应也是未知的，尤其是在儿童中。因此，我将通过使用多阵列细胞因子分析来表征不同类型运动的细胞因子特征，以同时评估多种细胞因子，并确定促炎症或抗炎细胞因子的平衡是否在男孩和男性之间有所不同。 目的4：最后，我将进行体外实验，以了解运动在肌肉发育过程中的抗炎作用。使用收集的血清作为目标3的一部分，我将运动血清与C2C12成肌细胞共同孵育，存在和不存在炎性细胞因子，肿瘤坏死因子-α。我们的初步研究结果表明，运动血清可以抑制肿瘤坏死因子-α对肌肉的负面影响。我们希望扩展这些令人兴奋的发现，并确定肌肉发育的其他哪些方面受到影响，以及涉及哪些途径。