Role of adenosine 5'-monophosphate-activated protein kinase in interleukin-6 release from isolated mouse skeletal muscle

Endocrinology. 2009 Feb;150(2):600-6. doi: 10.1210/en.2008-1204. Epub 2008 Sep 25.


IL-6 is released from skeletal muscle during exercise and has consequently been implicated to mediate beneficial effects on whole-body metabolism. Using 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), a pharmacological activator of 5'-AMP-activated protein kinase (AMPK), we tested the hypothesis that AMPK modulates IL-6 release from isolated muscle. Skeletal muscle from AMPKalpha2 kinase-dead transgenic, AMPKalpha1 knockout (KO) and AMPKgamma3 KO mice and respective wild-type littermates was incubated in vitro, in the absence or presence of 2 mmol/liter AICAR. Skeletal muscle from wild-type mice was also incubated with the AMPK activator A-769662. Incubation of mouse glycolytic extensor digitorum longus and oxidative soleus muscle for 2 h was associated with profound IL-6 mRNA production and protein release, which was suppressed by AICAR (P < 0.001). Basal IL-6 release from soleus was increased between AMPKalpha2 kinase-dead and AMPKalpha1 KO and their respective wild-type littermates (P < 0.05), suggesting AMPK participates in the regulation of IL-6 release from oxidative muscle. The effect of AICAR on muscle IL-6 release was similar between AMPKalpha2 KD, AMPKalpha1 KO, and AMPKgamma3 KO mice and their respective wild-type littermates (P < 0.001), indicating AICAR-mediated suppression of IL-6 mRNA expression and protein release is independent of AMPK function. However, IL-6 release from soleus, but not extensor digitorum longus, was reduced 45% by A-769662. Our results on basal and A-769662-mediated IL-6 release provide evidence for a role of AMPK in the regulation of IL-6 release from oxidative skeletal muscle. Furthermore, in addition to activating AMPK, AICAR suppresses IL-6 release by an unknown, AMPK-independent mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • AMP-Activated Protein Kinases / physiology*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Hypoglycemic Agents / pharmacology
  • Interleukin-6 / metabolism*
  • Ionomycin / pharmacology
  • Ionophores / pharmacology
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Organ Culture Techniques
  • Protein Subunits / genetics
  • Protein Subunits / physiology
  • Pyrones / pharmacology
  • Ribonucleotides / pharmacology
  • Thiophenes / pharmacology


  • A 769662
  • Hypoglycemic Agents
  • Interleukin-6
  • Ionophores
  • Protein Subunits
  • Pyrones
  • Ribonucleotides
  • Thiophenes
  • Aminoimidazole Carboxamide
  • Ionomycin
  • Prkag3 protein, mouse
  • AMP-Activated Protein Kinases
  • AICA ribonucleotide