title: Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK.
abstract: Although catabolic signaling has a well-established role in muscle wasting during cancer cachexia, the suppression of anabolic signaling also warrants further investigation. In cachectic tumor-bearing mice, circulating IL-6 levels are associated with suppressed muscle protein synthesis and mTORC1 signaling. We have found AMPK and IGF-I/insulin signaling, two well-known regulators of the mammalian target of rapamycin (mTOR), are altered with the progression of cachexia. How IL-6 can induce suppression of mTORC1 signaling remains to be established. The purpose of this study was to examine mTOR complex 1 (mTORC1) activation and regulation by IL-6 during cancer cachexia. IL-6 effects on mTOR activation were examined in Apc(Min/+) mouse skeletal muscle and C2C12 myotubes. Systemic IL-6 overexpression in Apc(Min/+) mice produced a dose-dependent suppression of mTOR signaling that corresponded to induction of STAT3 and AMPK phosphorylation. This result was also evident in IL-6-treated myotubes. Basal mTOR activation and mTOR responsiveness to glucose administration were suppressed in cachectic skeletal muscle. However, insulin induction of mTOR activity was maintained in IL-6-treated myotubes. Whereas IL-6 suppression of myotube mTOR activity was rescued by AMPK inhibition, inhibition of STAT3 signaling was not sufficient to rescue IL-6 suppression of mTOR activity. Last, treadmill exercise training was able to prevent IL-6-induced inhibition of mTOR signaling in Apc(Min/+) mice independently of activated STAT. In conclusion, we report dose-dependent suppression of mTOR activity by IL-6 and suppressed mTOR responsiveness to glucose administration in Apc(Min/+) mice. IL-6 suppression of mTOR activity was dependent on AMPK activation and independent of STAT signaling in myotubes.
authors.affiliation: Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia, South Carolina 29208, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: White
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Puppa
authors.forename: Song
authors.initials: S
authors.lastname: Gao
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Welle
authors.forename: James A
authors.initials: JA
authors.lastname: Carson
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002100:Cachexia / Q000201:enzymology / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D010805:Physical Conditioning, Animal / Q000502:physiology; D011506:Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
chemical_list: D015850:Interleukin-6; D046912:Multiprotein Complexes; D011506:Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C516138:dorsomorphin; D000620:Aminoimidazole Carboxamide; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMPK; IGF-I; IL-6; STAT; cachexia; colorectal cancer; exercise; inflammation; mTOR; muscle; protein synthesis; wasting