title: AICAR-induced activation of AMPK negatively regulates myotube hypertrophy through the HSP72-mediated pathway in C2C12 skeletal muscle cells.
abstract: 5'-AMP-activated protein kinase (AMPK) plays an important role as a negative regulator of skeletal muscle mass. However, the precise mechanism of AMPK-mediated regulation of muscle mass is not fully clarified. Heat shock proteins (HSPs), stress-induced molecular chaperones, are related with skeletal muscle adaptation, but the association between AMPK and HSPs in skeletal muscle hypertrophy is unknown. Thus, we investigated whether AMPK regulates hypertrophy by mediating HSPs in C2C12 cells. The treatment with AICAR, a potent stimulator of AMPK, decreased 72-kDa HSP (HSP72) expression, whereas there were no changes in the expressions of 25-kDa HSP, 70-kDa heat shock cognate, and heat shock transcription factor 1 in myotubes. Protein content and diameter were less in the AICAR-treated myotubes in those without treatment. AICAR-induced suppression of myotube hypertrophy and HSP72 expression was attenuated in the siRNA-mediated AMPKα knockdown myotubes. AICAR increased microRNA (miR)-1, a modulator of HSP72, and the increase of miR-1 was not induced in AMPKα knockdown condition. Furthermore, siRNA-mediated HSP72 knockdown blocked AICAR-induced inhibition of myotube hypertrophy. AICAR upregulated the gene expression of muscle Ring-finger 1, and this alteration was suppressed in either AMPKα or HSP72 knockdown myotubes. The phosphorylation of p70 S6 kinase Thr(389) was downregulated by AICAR, whereas this was attenuated in AMPKα, but not in HSP72, knockdown myotubes. These results suggest that AMPK inhibits hypertrophy through, in part, an HSP72-associated mechanism via miR-1 and protein degradation pathways in skeletal muscle cells.
authors.affiliation: Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Toyohashi, Japan;
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Egawa
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ohno
authors.forename: Ayumi
authors.initials: A
authors.lastname: Goto
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ikuta
authors.forename: Miho
authors.initials: M
authors.lastname: Suzuki
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Ohira
authors.forename: Shingo
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Takao
authors.initials: T
authors.lastname: Sugiura
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Ohira
authors.forename: Toshitada
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Goto
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D050884:HSP72 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006984:Hypertrophy / Q000139:chemically induced; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D050884:HSP72 Heat-Shock Proteins; D034741:RNA, Small Interfering; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide
keywords: acetyl-CoA carboxylase; atrogin-1; heat shock transcription factor 1; microRNA; muscle rRing-finger 1