Skeletal muscle gp130 receptor regulation of cancer cachexiainduced muscle mass loss

Circulating IL6 levels and skeletal muscle STAT3 activation are involved with muscle loss in many types of cancer cachexia. Additionally, cancerinduced muscle loss is attenuated by muscle STAT3 signaling inhibition. STAT3 is a downstream target of gp130 receptor (gp130r) signaling, and the gp130r also is involved in the initiation of intracellular IL6 signaling. The purpose of this study was to determine if the skeletal muscle gp130r initiates signaling necessary for cancerinduced muscle loss. PBS or Lewis lung carcinoma (LLC) cells were injected to 8 week old male wild type (WT) or skeletal muscle gp130r knockout mice (mgp130r). After ~30 days animal were sacrificed. Gastrocnemius muscle mass was decreased 27% in WT + LLC mice, but only 4% in mgp130r + LLC mice. Epididymal fat mass was reduced by LLC in WT (55%) and mgp130r mice (35%). LLCinduced suppression of muscle mTOR signaling was not improved in mgp130r mice. LLC elicited a 1.7 and 1.9 fold reduction of p4EBP1 in WT and mgp130r mice, respectively. Cytochrome C protein expression was reduced 2.4 fold in WT mice by LLC, and only 1.5 fold in mgp130r mice. These data demonstrate that in the LLC tumor model of cancer cachexia gp130r loss attenuated cancerinduced gastrocnemius muscle mass loss. This effect was not dependent on rescuing muscle mTOR signaling, but may involve attenuation of reduced oxidative capacity. Funded by R01CA121249

Skeletal muscle gp130 receptor regulation of cancer cachexiainduced muscle mass loss Academic Article