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Role of Adenosine 5'-Monophosphate-Activated Protein Kinase in Interleukin-6 Release from Isolated Mouse Skeletal Muscle

Department of Molecular Medicine and Surgery (S.G., Y.C.L., R.B., J.R.Z.), Section for Integrative Physiology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Copenhagen Muscle Research Center (J.T.T., J.F.W.), Department of Exercise and Sports Sciences, University of Copenhagen, DK-2400 Copenhagen, Denmark; Institute Cochin (B.V.), Université Paris Descartes, Centre National de la Recherche Scientifique (Unité Mixte de Recherche 8104), 75006 Paris, France; and Institut National de la Santé et de la Recherche Médicale, Unité 567 (B.V.), 75014 Paris, France

Address all correspondence and requests for reprints to: Juleen R. Zierath, Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, von Eulers väg 4, 4th Floor, S-171 77 Stockholm, Sweden. E-mail: juleen.zierath{at}ki.se.

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-β-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 AMPK2 kinase-dead transgenic, AMPK1 knockout (KO) and AMPK3 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 AMPK2 kinase-dead and AMPK1 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 AMPK2 KD, AMPK1 KO, and AMPK3 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.

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