title: Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin.
abstract: Sarcolemmal ATP-sensitive potassium (KATP) channels control skeletal muscle energy use through their ability to adjust membrane excitability and related cell functions in accordance with cellular metabolic status. Mice with disrupted skeletal muscle KATP channels exhibit reduced adipocyte size and increased fatty acid release into the circulation. As yet, the molecular mechanisms underlying this link between skeletal muscle KATP channel function and adipose mobilization have not been established. Here, we demonstrate that skeletal muscle-specific disruption of KATP channel function in transgenic (TG) mice promotes production and secretion of musclin. Musclin is a myokine with high homology to atrial natriuretic peptide (ANP) that enhances ANP signaling by competing for elimination. Augmented musclin production in TG mice is driven by a molecular cascade resulting in enhanced acetylation and nuclear exclusion of the transcription factor forkhead box O1 (FOXO1) - an inhibitor of transcription of the musclin encoding gene. Musclin production/secretion in TG is paired with increased mobilization of fatty acids and a clear trend toward increased circulating ANP, an activator of lipolysis. These data establish KATP channel-dependent musclin production as a potential mechanistic link coupling "local" skeletal muscle energy consumption with mobilization of bodily resources from fat. Understanding such mechanisms is an important step toward designing interventions to manage metabolic disorders including those related to excess body fat and associated co-morbidities.
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: ana-sierra@uiowa.edu.
authors.forename: Ana
authors.initials: A
authors.lastname: Sierra
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: ekaterina-subbotina@uiowa.edu.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Subbotina
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: zhiyong-zhu@uiowa.edu.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: zhan-gao@uiowa.edu.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: sivaramakrishna.koganti@ttuhc.edu.
authors.forename: Siva Rama Krishna
authors.initials: SR
authors.lastname: Koganti
authors.affiliation: Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA. Electronic address: william.coetzee@nyumc.org.
authors.forename: William A
authors.initials: WA
authors.lastname: Coetzee
authors.affiliation: Center for Regenerative Biology, Department of Molecular and Cell Biology, Advanced Technology Laboratory, University of Connecticut, 1392 Storrs Road Unit 4243, Storrs, Connecticut 06269, USA. Electronic address: david.goldhamer@uconn.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Goldhamer
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, Iowa City, IA 52242, USA. Electronic address: denice-zingman@uiowa.edu.
authors.forename: Denice M
authors.initials: DM
authors.lastname: Hodgson-Zingman
authors.affiliation: Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA 52242, USA; Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, Iowa City, IA 52242, USA; Department of Veterans Affairs, Medical Center, Iowa City, IA 52242, USA. Electronic address: leonid-zingman@uiowa.edu.
authors.forename: Leonid V
authors.initials: LV
authors.lastname: Zingman
mesh_terms: D000818:Animals; D005260:Female; D015640:Ion Channel Gating / Q000502:physiology*; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D054086:KATP Channels; D009124:Muscle Proteins; C498449:Ostn protein, mouse; D014157:Transcription Factors
keywords: Action potential; Calcium; Endurance; Fatty acid; Natriuretic peptide
references.citation: Regul Pept. 2009 Feb 25;153(1-3):56-63
references.pmid: 19027799
references.citation: Physiol Genomics. 2005 Jul 14;22(2):204-12
references.pmid: 15914579
references.citation: Proc Natl Acad Sci U S A. 2015 Dec 29;112(52):16042-7
references.pmid: 26668395
references.citation: Exp Physiol. 2008 Oct;93(10):1126-38
references.pmid: 18586858
references.citation: J Endocrinol. 2009 May;201(2):287-95
references.pmid: 19244276
references.citation: Cell Metab. 2010 Jan;11(1):58-69
references.pmid: 20074528
references.citation: J Gen Physiol. 2014 Jan;143(1):119-34
references.pmid: 24344248
references.citation: Mol Cell. 2004 May 7;14(3):395-403
references.pmid: 15125842
references.citation: Biochem Biophys Res Commun. 2007 Dec 14;364(2):358-65
references.pmid: 17950246
references.citation: Mol Ther. 2015 Apr;23(4):707-16
references.pmid: 25648265
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 2):H2339-45
references.pmid: 8997291
references.citation: Cell. 2011 May 13;145(4):607-21
references.pmid: 21565617
references.citation: J Biol Chem. 2003 Dec 12;278(50):50563-71
references.pmid: 14523025
references.citation: Handb Exp Pharmacol. 2009;(191):341-66
references.pmid: 19089336
references.citation: FASEB J. 2000 Jul;14(10):1345-51
references.pmid: 10877827
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):13278-83
references.pmid: 12271142
references.citation: Mol Genet Metab. 2008 Nov;95(3):117-26
references.pmid: 18762440
references.citation: J Physiol. 2007 Jul 15;582(Pt 2):843-57
references.pmid: 17510189
references.citation: FEBS J. 2011 Jun;278(11):1808-17
references.pmid: 21375692
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7403-8
references.pmid: 10377427
references.citation: Am J Physiol Cell Physiol. 2003 Dec;285(6):C1464-74
references.pmid: 12917105
references.citation: Am J Physiol Heart Circ Physiol. 2006 Aug;291(2):H543-51
references.pmid: 16501027
references.citation: J Biol Chem. 2001 Jun 22;276(25):22064-70
references.pmid: 11303026
references.citation: Physiol Rev. 2010 Jul;90(3):799-829
references.pmid: 20664073
references.citation: J Physiol. 1994 Mar 15;475(3):495-507
references.pmid: 8006831
references.citation: EMBO J. 2003 Apr 15;22(8):1732-42
references.pmid: 12682006
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R257-65
references.pmid: 12069952
references.citation: Trends Endocrinol Metab. 2008 May-Jun;19(4):130-7
references.pmid: 18337116
references.citation: J Physiol. 2010 Nov 15;588(Pt 22):4549-62
references.pmid: 20855438
references.citation: Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E505-13
references.pmid: 18559985
references.citation: Cardiovasc Res. 2005 Jul 1;67(1):60-8
references.pmid: 15949470
references.citation: Diabetes. 2008 Dec;57(12):3199-204
references.pmid: 18835931
references.citation: Mol Cells. 2015 Apr;38(4):343-8
references.pmid: 25728750
references.citation: J Biol Chem. 2004 May 7;279(19):19391-5
references.pmid: 15044443