INTERACTION BETWEEN IL-6 AND THE GH/IGF-1 AXIS IN MUSCLE

肌肉中 IL-6 和 GH/IGF-1 轴之间的相互作用

• 批准号: 7800878
• 负责人: Gregory Nicholas Adams
• 金额: $ 35.29万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7800878
• 关键词: Address; Adult; Back; Child; Chronic; Data; Development; Dose; Elements; Event; Exercise; Feedback; Funding; Growth; Growth Factor; Growth and Development function; Health; Human; Hypertrophy; IL6 gene; Immune response; Infection; Inflammation; Infusion procedures; Insulin-Like Growth Factor I; Interleukin-6; Literature; Mediating; Mediator of activation protein; Methods; Modeling; Molecular; Monitor; Muscle; Muscular Atrophy; Physiological; Plasma; Process; Protocols documentation; Rattus; Role; Running; Signal Pathway; Signal Transduction; Skeletal Muscle; Somatomedins; Somatotropin; System; Time; base; cytokine; depressed; design; feeding; in vivo; research study; response; skeletal muscle growth

The growth hormone (GH) / insulin-like growth factor-l (IGF-I) axis is a powerful mediator of skeletal muscle growth. IGF-I is also known to be an important mediator of the adaptation of skeletal muscle to increased loading. The "proinflammatory" cytokine interleukin -6 (IL-6) is primarily involved with the immune response to infection. In many settings the functions of IL-6 are known to induse a catabolic state in skeletal muscle. There is evidence that some components of the intracellular signaling pathways that are activated by IGF-I and/or GH are shared with signaling stimulated by IL-6. These common elements include components of the JAK/STAT/SOCS signaling and negative feed back system. Paradoxically, common forms of exercise have been shown to increase plasma IL-6 and to depress circulating IGF-I. We present preliminary data which demonstrates that relatively low doses of IL-6, comparable to those seen in humans following exercise, can initiate a catabolic response in skeletal muscle. We hypothesize that elevated muscle levels of IL-6 interact with and negatively impact the anabolic effects of GH and IGF-I in skeletal muscle in vivo. We speculate that one of the mechanisms by which IL-6 mediates this impact is via the activation of SOCS feedback resulting in alterations in IGF-I and GH mediated intracellular signals. We propose experiments designed to:1) characterize IL-6 signaling in muscle; 2) characterize GH signaling in muscle; 3) identify the mechanisms by which IL-6 interacts with and alters GH and IGF-I signaling; 4) identify the mechanisms by which IL-6 interacts with and alters the adaptation of skeletal muscle to increased loading ; 5) identify the mechanisms by which IL-6 impacts the growth and development of skeletal muscle. Our approach is based on the in vivo local muscle infusion model developed by our team. In contrast to the methods currently found in the literature, this approach allows for the direct (i.e., non-systemic) delivery of growth factors and cytokines into a single targeted skeletal muscle. In our previous funding period we demonstrated that this approach can be used to manipulate intracellular signaling pathways and allow for the identification of mechanisms that mediate the response to growth factors. The studies outlined in this proposal will add to our understanding of the role of exercise induced elevations in IL-6 with regard to its impacts on muscle growth and adaptation.

生长激素(GH)/胰岛素样生长因子-L(IGFI)轴是骨骼肌的强大介体 成长。IGF-I也被认为是骨骼肌适应增加的一个重要中介。 正在装车。促炎症细胞因子白介素6(IL-6)主要参与免疫反应。 与感染有关。在许多环境中，已知IL-6的功能导致骨骼肌处于分解代谢状态。 有证据表明，由IGF-I激活的细胞内信号通路的某些组成部分 和/或GH与IL-6刺激的信号转导相同。这些公共元素包括 JAK/STAT/SOCS信令和负反馈系统。矛盾的是，常见的锻炼形式 已被证明可以升高血浆IL-6和抑制循环中的IGF-I。我们提供了初步数据， 表明相对较低剂量的IL-6，与人体运动后的IL-6相当，可以 在骨骼肌中启动分解代谢反应。我们假设，肌肉中IL-6水平升高会相互作用 并对体内骨骼肌中生长激素和胰岛素样生长因子-I的合成代谢作用产生负面影响。我们推测 IL-6介导这种影响的机制之一是通过激活SOCS反馈 IGF-I和GH介导的细胞内信号的改变。我们提出的实验旨在：1) 确定肌肉中IL-6信号的特征；2)确定肌肉中GH信号的特征；3)通过 哪些IL-6与GH和IGF-I信号相互作用并改变；4)确定IL-6通过哪些机制 与骨骼肌相互作用并改变其对增加负荷的适应；5)确定其机制 通过IL-6影响骨骼肌的生长发育。我们的方法是基于体内的 我们团队开发的局部肌肉输注模型。与当前在 文献报道，这种方法允许将生长因子和细胞因子直接(即，非系统地)输送到 单一的靶向骨骼肌。在我们之前的资助期中，我们证明了这种方法可以 用于操纵细胞内信号通路，并允许识别 调节对生长因素的反应。这项提案中概述的研究将增加我们的理解 运动诱导的IL-6升高对肌肉生长和适应的影响的作用。