title: Role of adenosine 5'-monophosphate-activated protein kinase in interleukin-6 release from isolated mouse skeletal muscle.
abstract: 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.
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Stephan
authors.initials: S
authors.lastname: Glund
authors.forename: Jonas T
authors.initials: JT
authors.lastname: Treebak
authors.forename: Yun Chau
authors.initials: YC
authors.lastname: Long
authors.forename: Romain
authors.initials: R
authors.lastname: Barres
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Jorgen F
authors.initials: JF
authors.lastname: Wojtaszewski
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D011753:Pyrones / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D015850:Interleukin-6; D007476:Ionophores; D021122:Protein Subunits; D011753:Pyrones; D012265:Ribonucleotides; D013876:Thiophenes; D000620:Aminoimidazole Carboxamide; D015759:Ionomycin; C526221:Prkag3 protein, mouse; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile