Muscle mTORC1 suppression by IL-6 during cancer cachexia

A role for AMPK

James P. White, Melissa J. Puppa, Song Gao, Shuichi Sato, Stephen L. Welle, James Carson

Research output: Contribution to journalArticle

48 Citations (Scopus)

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 ApcMin/+ mouse skeletal muscle and C2C12 myotubes. Systemic IL-6 overexpression in ApcMin/+ 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 ApcMin/+ 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 ApcMin/+ mice. IL-6 suppression of mTOR activity was dependent on AMPK activation and independent of STAT signaling in myotubes.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume304
Issue number10
DOIs
StatePublished - May 15 2013

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Cachexia
AMP-Activated Protein Kinases
Sirolimus
Interleukin-6
Muscles
Skeletal Muscle Fibers
Neoplasms
Skeletal Muscle
Insulin
Glucose
Muscle Proteins
Insulin-Like Growth Factor I

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

Cite this

Muscle mTORC1 suppression by IL-6 during cancer cachexia : A role for AMPK. / White, James P.; Puppa, Melissa J.; Gao, Song; Sato, Shuichi; Welle, Stephen L.; Carson, James.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 304, No. 10, 15.05.2013.

Research output: Contribution to journalArticle

White, James P. ; Puppa, Melissa J. ; Gao, Song ; Sato, Shuichi ; Welle, Stephen L. ; Carson, James. / Muscle mTORC1 suppression by IL-6 during cancer cachexia : A role for AMPK. In: American Journal of Physiology - Endocrinology and Metabolism. 2013 ; Vol. 304, No. 10.
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