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.
Cachexia is a condition of whole body wasting that leads to loss of both muscle and adipose tissue and accounts for 20-40% of cancer-related deaths in the USA. We originally identified increased inflammation related to the underlying cancer as a cause of skeletal muscle loss, and our current proposal seeks to better understand how inflammation induces this loss during the progression of cancer cachexia. Understanding this process should lead to targeted therapies to prevent the progression of cachexia, allowing for the underlying cancer to be treated more effectively and increasing patient survival.
|Narsale, Aditi A; Puppa, Melissa J; Hardee, Justin P et al. (2016) Short-term pyrrolidine dithiocarbamate administration attenuates cachexia-induced alterations to muscle and liver in ApcMin/+ mice. Oncotarget 7:59482-59502|
|Carson, James A; Hardee, Justin P; VanderVeen, Brandon N (2016) The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting. Semin Cell Dev Biol 54:53-67|
|Gao, Song; Carson, James A (2016) Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes. Am J Physiol Cell Physiol 310:C66-79|
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|Carson, James A; Manolagas, Stavros C (2015) Effects of sex steroids on bones and muscles: Similarities, parallels, and putative interactions in health and disease. Bone 80:67-78|
|Hetzler, Kimbell L; Hardee, Justin P; Puppa, Melissa J et al. (2015) Sex differences in the relationship of IL-6 signaling to cancer cachexia progression. Biochim Biophys Acta 1852:816-25|
|Narsale, Aditi A; Carson, James A (2014) Role of interleukin-6 in cachexia: therapeutic implications. Curr Opin Support Palliat Care 8:321-7|
|Puppa, Melissa J; Gao, Song; Narsale, Aditi A et al. (2014) Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma-induced cachexia. FASEB J 28:998-1009|
|VelÃ¡zquez, Kandy T; Enos, Reilly T; Narsale, Aditi A et al. (2014) Quercetin supplementation attenuates the progression of cancer cachexia in ApcMin/+ mice. J Nutr 144:868-75|
|Puppa, Melissa J; Murphy, E Angela; Fayad, Raja et al. (2014) Cachectic skeletal muscle response to a novel bout of low-frequency stimulation. J Appl Physiol (1985) 116:1078-87|
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