IL6induced Cachexia and Muscle IGF1 Signaling
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Inflammatory cytokine IL6 is necessary for the development and progression of cancer cachexia in the ApcMin/+ mouse, a model of colorectal cancer and cachexia. The purpose of this study is to determine if circulating IL6 overexpression (OE) regulates muscle protein synthesis and associated IGF1 signaling in wild type (Wt) and ApcMin/+ mice. Twelve week, weight stable, male ApcMin/+ and Wt mice were randomly assigned to IL6 OE or control groups. Circulating IL6 OE was induced by electroporation of an IL6 expressing vector into the quadriceps muscle while an empty vector served as the control. At the end of the 2 week OE period, mice were given an IP injection of deuteriumlabeled phenylalanine to measure myofibrillar protein synthesis rates. IL6 OE reduced ApcMin/+ mice body weight 14% over the 2 week time period. ApcMin/+ mice overexpressing IL6 had a 16% decrease in gastrocnemius mass when compared to controls. Body and muscle weights in Wt mice were not affected by IL6 OE. ApcMin/+ mice had a 90% reduction in muscle IGF1 mRNA expression and an 80% reduction in the phosphorylation of eIF 4EBP1 protein. Myofibrillar protein synthesis was reduced 53% in the ApcMin/+ mouse overexpressing IL6. There was no difference in protein synthesis in the Wt mice. IL6 OE can accelerate cachexia in the ApcMin/+ mouse, in part, through the repression of muscle IGF1 signaling and muscle protein synthesis. R01CA12124901A2
