Anti-inflammatory mechanisms of exercise during human growth

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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.