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Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK

James P White1, Melissa J Puppa, Song Gao

  • 1Integrative Muscle Biology Laboratory, Exercise Science Department, University of South Carolina, Columbia, South Carolina 29208, USA.

American Journal of Physiology. Endocrinology and Metabolism
|March 28, 2013
PubMed

Insights

Interleukin-6 (IL-6) suppresses muscle protein synthesis in cancer cachexia by activating AMP-activated protein kinase (AMPK), which inhibits mTORC1 signaling. Exercise training can prevent this IL-6-induced suppression.

Area of Science:

  • Muscle physiology
  • Cancer biology
  • Molecular signaling

Background:

  • Cancer cachexia involves muscle wasting, with both catabolic and anabolic signaling pathways implicated.
  • Interleukin-6 (IL-6) is linked to suppressed muscle protein synthesis and mTORC1 signaling in cachectic mice.
  • AMP-activated protein kinase (AMPK) and IGF-I/insulin signaling are key regulators of mammalian target of rapamycin (mTOR) and are altered during cachexia progression.

Purpose of the Study:

  • To investigate the role of IL-6 in suppressing mTOR complex 1 (mTORC1) activation during cancer cachexia.
  • To elucidate the specific molecular mechanisms by which IL-6 impacts mTORC1 signaling in skeletal muscle.

Main Methods:

  • Examined mTORC1 activation and regulation by IL-6 in Apc(Min/+) mouse skeletal muscle and C2C12 myotubes.
  • Assessed the effects of systemic IL-6 overexpression and IL-6 treatment on signaling pathways (STAT3, AMPK, mTOR).
  • Investigated the impact of AMPK and STAT3 inhibition, as well as exercise training, on IL-6-mediated mTOR suppression.

Main Results:

  • Systemic IL-6 overexpression in Apc(Min/+) mice caused a dose-dependent suppression of mTOR signaling, linked to increased STAT3 and AMPK phosphorylation.
  • IL-6 treatment of myotubes mimicked these effects, suppressing basal mTOR activation and responsiveness to glucose.
  • IL-6-induced suppression of myotube mTOR activity was rescued by AMPK inhibition but not STAT3 inhibition.
  • Insulin-induced mTOR activation remained intact in IL-6-treated myotubes.
  • Treadmill exercise training prevented IL-6-induced mTOR inhibition in mice, independent of STAT activation.

Conclusions:

  • IL-6 directly suppresses mTORC1 activity in a dose-dependent manner during cancer cachexia.
  • The suppression of mTORC1 by IL-6 is mediated through AMPK activation and is independent of STAT signaling.
  • mTORC1 responsiveness to glucose is impaired in cachectic muscle, while insulin signaling remains functional.
  • Exercise training offers a potential therapeutic strategy to counteract IL-6-induced mTOR inhibition in cancer cachexia.
Keywords:
AMPKIGF-IIL-6STATcachexiacolorectal cancerexerciseinflammationmTORmuscleprotein synthesiswasting

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