IL‐6‐induced Cachexia and Muscle IGF‐1 Signaling

Abstract

Inflammatory cytokine IL‐6 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 IL‐6 over‐expression (OE) regulates muscle protein synthesis and associated IGF‐1 signaling in wild type (Wt) and ApcMin/+ mice. Twelve week, weight stable, male ApcMin/+ and Wt mice were randomly assigned to IL‐6 OE or control groups. Circulating IL‐6 OE was induced by electroporation of an IL‐6 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 deuterium‐labeled phenylalanine to measure myofibrillar protein synthesis rates. IL‐6 OE reduced ApcMin/+ mice body weight 14% over the 2 week time period. ApcMin/+ mice over‐expressing IL‐6 had a 16% decrease in gastrocnemius mass when compared to controls. Body and muscle weights in Wt mice were not affected by IL‐6 OE. ApcMin/+ mice had a 90% reduction in muscle IGF‐1 mRNA expression and an 80% reduction in the phosphorylation of eIF 4EBP‐1 protein. Myofibrillar protein synthesis was reduced 53% in the ApcMin/+ mouse over‐expressing IL‐6. There was no difference in protein synthesis in the Wt mice. IL‐6 OE can accelerate cachexia in the ApcMin/+ mouse, in part, through the repression of muscle IGF‐1 signaling and muscle protein synthesis. R01CA121249‐01A2