Trans IL‐6 signaling and suppressed muscle protein synthesis with cancer (1163.11)

Abstract

Systemic inflammation is associated with many types of cancer‐induced cachexia, and often includes increased IL‐6 levels. Tissue STAT3 activation can occur by classical or trans IL‐6 signaling. Inhibition of IL‐6 or muscle STAT3 can attenuate cachexia muscle mass loss in tumor bearing mice. The purpose of this study was to determine if inhibition of either trans IL‐6 or systemic STAT3/NfκB signaling could improve cancer‐induced suppression of muscle protein synthesis in ApcMin/+ (Min) mice. After the initiation of cachexia Min mice were randomized to receive sgp130Fc (150ug/wk) to inhibit trans IL‐6 signaling, PDTC (10mg/kg/day) to inhibit STAT3/NfκB signaling, or PBS for 2‐wks. At 16 weeks of age Min mice had lost 7% body weight (BW). Administration of PDTC or sgp130Fc attenuated further BW loss, while PBS mice lost an additional 8% BW. Additionally, PDTC and sgp130Fc attenuated the cachexia‐mediated loss of gastrocnemius muscle mass. While sgp130Fc was unable to attenuate cachexia suppression of muscle protein synthesis, PDTC administration increased muscle protein synthesis. In summary, trans IL‐6 signaling inhibition was sufficient to attenuate cancer‐induced muscle mass loss independent of effects on suppressed muscle protein synthesis, while global STAT3 and NfκB inhibition rescued both muscle mass and protein synthesis during cancer cachexia.Grant Funding Source: Supported by R01CA121249