Cachexia, or progressive wasting of fat and skeletal muscle despite adequate nutrition, is a devastating complication of cancer. Cachexia results in weakness, diminished quality of life, poor response to therapy, and susceptibility to illness. Cachexia afflicts more than half of all cancer patients and is responsible for 25-30% of all cancer-related deaths. Currently, there are no approved effective treatments for muscle wasting in cancer. In cancer patients, cachexia and mortality correlate closely with elevated serum IL-6 levels. In mice, IL-6 administration causes systemic wasting and IL-6 inhibition ameliorates cancer cachexia. However, the molecular mechanisms linking IL-6 and skeletal muscle wasting are unknown. Our long term goal is to establish the key regulatory pathways that mediate muscle wasting in cancer for the purpose of developing therapeutics. The objective of this application is to elucidate the mechanisms by which IL-6 results in skeletal muscle wasting in cancer. Our hypothesis is that IL-6 signaling in mature myofibers activates STAT3 and STAT3 target genes that together result in increased proteolysis and reduced hypertrophy. The net result is myofiber wasting. We base this hypothesis on considerable preliminary data. In skeletal muscle of 5 mouse models of cachexia, we have observed phosphorylated STAT3 and expression of known STAT3 target genes, including acute phase proteins. The IL-6/STAT3 transcriptome is also activated in skeletal muscle from patients with pancreatic cancer cachexia. We show that constitutively activated STAT3 is sufficient to cause wasting in myofibers and normal mouse skeletal muscle. Furthermore, over-expression of STAT3 inhibitors, abrogated IL-6-induced wasting of myotubes. Taken together, these results strongly implicate STAT3 as a causative factor in muscle wasting in cancer cachexia. The studies proposed here will determine definitively the role of the IL-6/gp130/STAT3 signaling pathway in muscle growth regulation in mature myofibers, both in normal physiology and in cancer cachexia. When these studies are complete, we will have identified potential targets for muscle preservation in cancer cachexia, as well as new regulators of skeletal muscle growth.
The specific aims of this study are as follows: 1) Determine the role of the IL-6/STAT3 pathway and target genes in myotube hypertrophy and wasting in vitro, 2) Determine STAT3 and target gene functions in regulating mature myofiber growth in normal mice and in mouse models of cancer cachexia, and 3) Determine the contribution of skeletal muscle STAT3 to IL-6 induced wasting and cancer cachexia using skeletal muscle specific STAT3 null mice and our panel of MLC-SOCS3 transgenics.
Muscle wasting in cancer is associated with high levels of Interleukin-6, a blood-borne protein involved in inflammation and host defense. Using cell culture and mouse models, this study will determine how Interleukin- 6 activates muscle wasting in cancer in order to identify future therapeutic targets.
|Milgrom, Daniel P; Koniaris, Leonidas G; Valsangkar, Nakul P et al. (2017) An Assessment of the Academic Impact of Shock Society Members. Shock :|
|Sato, Amy Y; Richardson, Danielle; Cregor, Meloney et al. (2017) Glucocorticoids Induce Bone and Muscle Atrophy by Tissue-Specific Mechanisms Upstream of E3 Ubiquitin Ligases. Endocrinology 158:664-677|
|Bell, Teresa M; Valsangkar, Nakul; Joshi, Mugdha et al. (2017) The Role of PhD Faculty in Advancing Research in Departments of Surgery. Ann Surg 265:111-115|
|Milgrom, Daniel P; Lad, Neha L; Koniaris, Leonidas G et al. (2017) Bone Pain and Muscle Weakness in Cancer Patients. Curr Osteoporos Rep 15:76-87|
|Barreto, Rafael; Mandili, Giorgia; Witzmann, Frank A et al. (2016) Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways. Front Physiol 7:472|
|Bonetto, Andrea; Rupert, Joseph E; Barreto, Rafael et al. (2016) The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia. J Vis Exp :|
|Au, Ernie D; Desai, Aditya P; Koniaris, Leonidas G et al. (2016) The MEK-Inhibitor Selumetinib Attenuates Tumor Growth and Reduces IL-6 Expression but Does Not Protect against Muscle Wasting in Lewis Lung Cancer Cachexia. Front Physiol 7:682|
|Zimmers, Teresa A; Fishel, Melissa L; Bonetto, Andrea (2016) STAT3 in the systemic inflammation of cancer cachexia. Semin Cell Dev Biol 54:28-41|
|Barreto, Rafael; Waning, David L; Gao, Hongyu et al. (2016) Chemotherapy-related cachexia is associated with mitochondrial depletion and the activation of ERK1/2 and p38 MAPKs. Oncotarget 7:43442-43460|
|Bell, Teresa M; Valsangkar, Nakul; Joshi, Mugdha et al. (2016) The Role of PhD Faculty in Advancing Research in Departments of Surgery. Ann Surg :|
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