title: Irisin, a Novel Myokine, Regulates Glucose Uptake in Skeletal Muscle Cells via AMPK.
abstract: Irisin is a novel myokine produced by skeletal muscle. However, its metabolic role is poorly understood. In the present study, irisin induced glucose uptake in differentiated skeletal muscle cells. It increased AMP-activated protein kinase (AMPK) phosphorylation and the inhibition of AMPK blocked glucose uptake. It also increased reactive oxygen species (ROS) generation. N-acetyl cysteine, a ROS scavenger, blocked irisin-induced AMPK phosphorylation. Moreover, irisin activated p38 MAPK in an AMPK-dependent manner. The inhibition and knockdown of p38 MAPK blocked irisin-induced glucose uptake. A colorimetric absorbance assay showed that irisin stimulated the translocation of glucose transporter type 4 to the plasma membrane and that this effect was suppressed in cells pretreated with a p38 MAPK inhibitor or p38 MAPK small interfering RNA. In primary cultured myoblast cells, irisin increased the concentration of intracellular calcium. STO-609, a calcium/calmodulin-dependent protein kinase kinase inhibitor, blocked irisin-induced AMPK phosphorylation, implying that calcium is involved in irisin-mediated signaling. Our results suggest that irisin plays an important role in glucose metabolism via the ROS-mediated AMPK pathway in skeletal muscle cells.
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Jung Ok
authors.initials: JO
authors.lastname: Lee
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Nami
authors.initials: N
authors.lastname: Kim
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Joong Kwan
authors.initials: JK
authors.lastname: Kim
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Hyung Ip
authors.initials: HI
authors.lastname: Kim
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Yong Woo
authors.initials: YW
authors.lastname: Lee
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Choi
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Oh
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.lastname: Suyeon-Hwang
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Sun Hwa
authors.initials: SH
authors.lastname: Park
authors.affiliation: Department of Anatomy (H.J.L., J.O.L., N.K., J.K.K., H.I.K., Y.W.L., S.J.K., S.H.P., H.S.K.), Korea University College of Medicine, Seoul, Korea 136-705; Division of Cardiology (J.-I.C.), Department of Internal Medicine, Korea University Medical Center, Seoul, Korea; College of Nursing (Y.O.), Korea University, Seoul, Korea 136-705; College of Pre-Pharm·Med (J.H.K.), DukSung Women's University, Seoul, Korea 132-714; and College of Pharmacy (S.-H.), University of Rhode Island, Kingston, Rhode Island 02881.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005353:Fibronectins / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology*; D032446:Myoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005353:Fibronectins; D051275:Glucose Transporter Type 4; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
references.citation: Biochem Biophys Res Commun. 2005 Jul 8;332(3):885-91
references.pmid: 15913551
references.citation: Eur J Biochem. 1997 Jun 1;246(2):259-73
references.pmid: 9208914
references.citation: Adipocyte. 2012 Jul 1;1(3):164-167
references.pmid: 23700527
references.citation: J Clin Invest. 1997 Oct 1;100(7):1831-9
references.pmid: 9312184
references.citation: Diabetes. 2006 Oct;55(10 ):2688-97
references.pmid: 17003332
references.citation: Diabetes. 2014 Feb;63(2):514-25
references.pmid: 24150604
references.citation: Circulation. 2008 Jun 17;117(24):3099-108
references.pmid: 18519848
references.citation: FASEB J. 2001 Apr;15(6):958-69
references.pmid: 11292656
references.citation: Biochim Biophys Acta. 2000 Jun 21;1492(1):203-6
references.pmid: 10858549
references.citation: Diabetes. 1998 Aug;47(8):1369-73
references.pmid: 9703344
references.citation: J Clin Endocrinol Metab. 2013 Dec;98(12):4899-907
references.pmid: 24057291
references.citation: Cell Metab. 2005 Jul;2(1):21-33
references.pmid: 16054096
references.citation: Recent Pat Biotechnol. 2012 Dec;6(3):167-71
references.pmid: 23092437
references.citation: Diabetes. 1996 Jan;45(1):28-36
references.pmid: 8522056
references.citation: Eur J Endocrinol. 2013 Oct 21;169(6):829-34
references.pmid: 24062354
references.citation: Science. 1994 May 13;264(5161):965-8
references.pmid: 8178155
references.citation: Diabetologia. 1998 Jun;41(6):724-30
references.pmid: 9662057
references.citation: Mol Cell. 2001 May;7(5):1085-94
references.pmid: 11389854
references.citation: J Biol Chem. 2003 May 16;278(20):17953-62
references.pmid: 12637564
references.citation: Diabetol Metab Syndr. 2014 Dec 05;6(1):133
references.pmid: 25530809
references.citation: Am J Physiol Cell Physiol. 2010 Apr;298(4):C807-16
references.pmid: 20089933
references.citation: J Hepatol. 2013 Sep;59(3):557-62
references.pmid: 23665283
references.citation: Biochem J. 2001 Nov 1;359(Pt 3):639-49
references.pmid: 11672439
references.citation: Neuroscience. 2013 Jun 14;240:155-62
references.pmid: 23470775
references.citation: Aging (Albany NY). 2013 Jul;5(7):515-30
references.pmid: 24018842
references.citation: EMBO J. 2005 May 18;24(10):1810-20
references.pmid: 15889149
references.citation: Nature. 2012 Jan 11;481(7382):463-8
references.pmid: 22237023
references.citation: Mol Cell Biol. 2006 Nov;26(22):8217-27
references.pmid: 16966378
references.citation: J Clin Endocrinol Metab. 2013 Apr;98(4):E769-78
references.pmid: 23436919
references.citation: J Exp Biol. 2011 Jan 15;214(Pt 2):337-46
references.pmid: 21177953
references.citation: Cell Signal. 2010 Apr;22(4):590-9
references.pmid: 19932174
references.citation: Peptides. 2014 Apr;54:89-100
references.pmid: 24472856
references.citation: Physiol Rev. 2008 Oct;88(4):1379-406
references.pmid: 18923185
references.citation: Nat Immunol. 2014 Oct;15(10):965-72
references.pmid: 25151490
references.citation: J Physiol. 2008 Apr 15;586(8):2195-201
references.pmid: 18292129
references.citation: PLoS One. 2013 Sep 02;8(9):e72858
references.pmid: 24023786
references.citation: Stem Cell Res. 2012 May;8(3):346-56
references.pmid: 22286010
references.citation: J Biol Chem. 2013 Nov 22;288(47):33738-44
references.pmid: 24114836
references.citation: J Biol Chem. 2004 May 7;279(19):19391-5
references.pmid: 15044443
references.citation: J Biol Chem. 2008 Nov 21;283(47):32802-11
references.pmid: 18718903
references.citation: Cell Metab. 2005 Jul;2(1):9-19
references.pmid: 16054095
references.citation: FASEB J. 2013 May;27(5):1981-9
references.pmid: 23362117
references.citation: J Physiol. 2006 Aug 15;575(Pt 1):251-62
references.pmid: 16777943
references.citation: J Appl Physiol (1985). 2007 Sep;103(3):1093-8
references.pmid: 17347387