Cachexia in ApcMin/+ mice: The role of IL-6

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DESCRIPTION (provided by applicant): Cancer cachexia, the unintentional loss of bodyweight and muscle mass, directly impacts patient survival and quality of life. The role of skeletal muscle in maintaining health, for cancer patients and healthy individuals, involves both the amount of muscle mass and the quality of the muscle, as it relates to metabolic capacity and substrate utilization flexibility. Although understanding muscle mass loss is a major focus of cachexia research, reduced muscle quality likely plays a role in both cachexia progression and mass loss. Understanding how the cancer patient's systemic environment disrupts both muscle metabolism and protein turnover regulation remains a challenge that is substantial enough to have impeded cancer cachexia treatment. Inflammatory cytokine IL-6 and muscle STAT signaling are clear regulators of muscle wasting in tumor-bearing mice. Muscle protein synthesis through mTOR is also suppressed in cachectic muscle. However, significant gaps remain in our understanding of the IL-6 regulation of suppressed muscle anabolic signaling with cancer cachexia. This proposal mechanistically extends our published and preliminary data examining IL-6 regulation of muscle protein turnover during the progression of cachexia. Our long-term goal is to improve cancer patient survival through understanding inflammatory, metabolic and hormonal signaling pathway interactions that disrupt muscle protein synthesis. Our study's overall objective is to mechanistically understand how the IL-6 family of cytokines can regulate nutrient, hormonal, and mechanical control of muscle protein turnover during the initiation and progression of cachexia in ApcMin/+ and Lewis Lung Carcinoma (LLC) implanted mice. Our central hypothesis is that muscle protein synthesis suppression through mTOR signaling is fundamental for cachexia- induced muscle mass loss. The rationale for this proposed research is that the identification of metabolic signaling pathways and the inflammatory regulators of these processes will allow therapeutic countermeasures that can block or reverse the progression of muscle wasting with cancer. Guided by our prior research and preliminary data using ApcMin/+ and LLC mouse cachexia models, we plan to test our central hypothesis and accomplish the objectives of this application with three specific aims: 1) Identify the IL-6 regulation of protein synthesis and mTOR signaling necessary for anabolic resistance to feeding and exercise during the progression of cachexia; 2) Determine if alterations in muscle oxidative metabolism regulate mTOR signaling and protein synthesis during the progression of cachexia; and 3) Determine if suppressed testosterone and androgen-associated signaling regulate mTOR signaling and protein turnover during the progression of cachexia. This research is innovative because it will examine mechanical, metabolic, and hormonal signaling pathways that are regulated by chronic systemic inflammation and control mTOR-signaling regulation of muscle protein synthesis with cachexia. It is significant because the results will lead to developing physical activity and pharmaceutical interventions that can intervene in the progression of muscle wasting with cancer.