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.
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