Journal
ENDOCRINOLOGY
Volume 150, Issue 2, Pages 600-606Publisher
ENDOCRINE SOC
DOI: 10.1210/en.2008-1204
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Funding
- Swedish Research Council
- Swedish Diabetes Association
- Foundation for Scientific Studies of Diabetology
- Swedish Centre for Sports Research
- Danish Medical Research Council
- Novo Nordisk Foundation
- Danish Diabetes Association
- Copenhagen Muscle Research Centre
- Strategic Research Foundation (INGVAR II)
- Commission of the European Communities [LSHM-CT-2004-005272 EXGENESIS, LSHM-CT-2004-512013 EUGENE2]
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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 AMPK alpha 2 kinase-dead transgenic, AMPK alpha 1 knockout (KO) and AMPK gamma 3 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 AMPK alpha 2 kinase-dead and AMPK alpha 1 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 AMPK alpha 2 KD, AMPK alpha 1 KO, and AMPK gamma 3 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. (Endocrinology 150: 600-606, 2009)
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