title: Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma-induced cachexia.
abstract: Chronic inflammation is associated with cachexia-induced skeletal muscle mass loss in cancer. Levels of IL-6 cytokine family members are increased during cancer-related cachexia and induce intracellular signaling through glycoprotein130 (gp130). Although muscle STAT3 and circulating IL-6 are implicated in cancer-induced muscle wasting, there is limited understanding of muscle gp130's role in this process. Therefore, we investigated the role of skeletal muscle gp130 (skm-gp130) in cancer-induced alterations in the regulation of muscle protein turnover. Lewis lung carcinoma (LLC) cells were injected into 8-wk-old skm-gp130-knockout (KO) mice or wild-type mice. Skeletal muscle loss was attenuated by 16% in gp130-KO mice, which coincided with attenuated LLC-induced phosphorylation of muscle STAT3, p38, and FOXO3. gp130 KO did not restore mTOR inhibition or alter AMP-activated protein kinase (AMPK) expression. The induction of atrogin expression and p38 phosphorylation in C2C12 myotubes exposed to LLC-treated medium was attenuated by gp130 inhibition, but mTOR inhibition was not restored. STAT signaling inhibition in LLC-treated myotubes did not attenuate the induction of p38 or AMPK phosphorylation. We concluded that, during LLC-induced cachexia, skm-gp130 regulates muscle mass signaling through STAT3 and p38 for the activation of FOXO3 and atrogin, but does not directly regulate the suppression of mTOR.
authors.affiliation: 1University of South Carolina, Department of Exercise Science, Public Health Research Center, Room 405, 921 Assembly Street, Columbia, SC 29208, USA. carsonj@mailbox.sc.edu.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Puppa
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: Aditi A
authors.initials: AA
authors.lastname: Narsale
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000209:etiology* / Q000378:metabolism*; D018827:Carcinoma, Lewis Lung / Q000150:complications* / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D016133:Polymerase Chain Reaction
chemical_list: D006023:Glycoproteins; D015850:Interleukin-6
keywords: C2C12 myotube; IL-6; STAT3; cancer; inflammation; protein turnover