title: Improved regenerative myogenesis and muscular dystrophy in mice lacking Mkp5.
abstract: Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in dystrophin. The degree of functional deterioration in muscle stem cells determines the severity of DMD. The mitogen-activated protein kinases (MAPKs), which are inactivated by MAPK phosphatases (MKPs), represent a central signaling node in the regulation of muscle stem cell function. Here we show that the dual-specificity protein phosphatase DUSP10/MKP-5 negatively regulates muscle stem cell function in mice. MKP-5 controlled JNK to coordinate muscle stem cell proliferation and p38 MAPK to control differentiation. Genetic loss of Mkp5 in mice improved regenerative myogenesis and dystrophin-deficient mdx mice lacking Mkp5 exhibited an attenuated dystrophic muscle phenotype. Hence, enhanced promyogenic MAPK activity preserved muscle stem cell function even in the absence of dystrophin and ultimately curtailed the pathogenesis associated with DMD. These results identify MKP-5 as an essential negative regulator of the promyogenic actions of the MAPKs and suggest that MKP-5 may serve as a target to promote muscle stem cell function in the treatment of degenerative skeletal muscle diseases.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Shi
authors.forename: Mayank
authors.initials: M
authors.lastname: Verma
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003433:Crosses, Genetic; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D016189:Dystrophin / Q000235:genetics; D005260:Female; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology; D009132:Muscles / Q000166:cytology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D012038:Regeneration; D013234:Stem Cells / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016189:Dystrophin; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C505617:Dusp10 protein, mouse; D054637:Dual-Specificity Phosphatases
references.citation: Curr Opin Neurol. 2002 Oct;15(5):539-44
references.pmid: 12351997
references.citation: Genes Dev. 2006 Jul 1;20(13):1692-708
references.pmid: 16818602
references.citation: FASEB J. 2008 Aug;22(8):2990-3000
references.pmid: 18417546
references.citation: Cell Metab. 2006 Jul;4(1):61-73
references.pmid: 16814733
references.citation: EMBO J. 2009 Oct 7;28(19):2896-907
references.pmid: 19696743
references.citation: J Biol Chem. 1997 Mar 7;272(10):6653-62
references.pmid: 9045696
references.citation: J Clin Invest. 2009 Dec;119(12):3817-29
references.pmid: 19920356
references.citation: Pharmacol Rev. 2008 Sep;60(3):261-310
references.pmid: 18922965
references.citation: J Biol Chem. 1995 Feb 24;270(8):4093-100
references.pmid: 7876159
references.citation: Mol Cell Biol. 1999 Jul;19(7):5203-17
references.pmid: 10373569
references.citation: Cell. 2010 Dec 23;143(7):1059-71
references.pmid: 21145579
references.citation: J Clin Invest. 2010 Jan;120(1):11-9
references.pmid: 20051632
references.citation: Science. 2005 Sep 23;309(5743):2064-7
references.pmid: 16141372
references.citation: Microsc Res Tech. 2000 Feb 1-15;48(3-4):127-30
references.pmid: 10679960
references.citation: FASEB J. 2010 Aug;24(8):2985-97
references.pmid: 20371627
references.citation: J Mol Med (Berl). 2010 Feb;88(2):155-66
references.pmid: 19816663
references.citation: J Cell Physiol. 2001 Jan;186(1):104-15
references.pmid: 11147804
references.citation: Curr Opin Genet Dev. 2008 Aug;18(4):330-6
references.pmid: 18625314
references.citation: J Cell Sci. 2006 Nov 15;119(Pt 22):4607-15
references.pmid: 17093265
references.citation: Mol Cell Biol. 1996 Nov;16(11):5964-73
references.pmid: 8887626
references.citation: Mol Cell Biol. 2005 Jun;25(11):4792-803
references.pmid: 15899879
references.citation: J Biol Chem. 1999 Jul 9;274(28):19949-56
references.pmid: 10391943
references.citation: Am J Physiol Cell Physiol. 2009 May;296(5):C1040-8
references.pmid: 19295173
references.citation: Nature. 2004 Aug 12;430(7001):793-7
references.pmid: 15306813
references.citation: J Cell Biol. 2005 Apr 11;169(1):105-16
references.pmid: 15824134
references.citation: Mol Biol Cell. 2008 Apr;19(4):1519-28
references.pmid: 18256287
references.citation: Cell. 2005 Sep 9;122(5):659-67
references.pmid: 16143100
references.citation: J Biol Chem. 2007 Feb 2;282(5):3058-65
references.pmid: 17158101
references.citation: J Biol Chem. 1998 Apr 24;273(17):10436-44
references.pmid: 9553102
references.citation: Cell. 1987 Dec 24;51(6):919-28
references.pmid: 3319190
references.citation: Dev Biol. 2000 Feb 15;218(2):115-24
references.pmid: 10656756
references.citation: Oncogene. 2007 May 14;26(22):3203-13
references.pmid: 17496916
references.citation: Muscle Nerve. 2012 Apr;45(4):552-61
references.pmid: 22431089
references.citation: Cell Stem Cell. 2010 Feb 5;6(2):117-29
references.pmid: 20144785
references.citation: Mol Cell Biol. 2007 Oct;27(20):7248-65
references.pmid: 17709384
references.citation: Oncogene. 1999 Nov 25;18(50):6981-8
references.pmid: 10597297
references.citation: Oncogene. 1995 Jan 5;10(1):159-66
references.pmid: 7824268
references.citation: Oncogene. 1997 Feb 13;14(6):697-704
references.pmid: 9038377
references.citation: Proc Natl Acad Sci U S A. 1983 Aug;80(15):4856-60
references.pmid: 6576361
references.citation: Cold Spring Harb Symp Quant Biol. 2008;73:323-31
references.pmid: 19329572
references.citation: J Appl Physiol (1985). 2001 Aug;91(2):534-51
references.pmid: 11457764
references.citation: J Cell Biol. 2007 Sep 10;178(6):1039-51
references.pmid: 17785520
references.citation: EMBO J. 2007 Mar 7;26(5):1245-56
references.pmid: 17304211
references.citation: Science. 1997 Nov 14;278(5341):1288-91
references.pmid: 9360925
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3710-4
references.pmid: 8475120
references.citation: J Biol Chem. 2008 Aug 22;283(34):23224-34
references.pmid: 18552402
references.citation: J Biol Chem. 1999 Feb 12;274(7):4341-6
references.pmid: 9933636
references.citation: Mol Biol Cell. 1999 Oct;10(10):3137-50
references.pmid: 10512856
references.citation: Dev Dyn. 1997 Apr;208(4):505-15
references.pmid: 9097022
references.citation: Am J Physiol Cell Physiol. 2007 May;292(5):C1681-9
references.pmid: 17151143
references.citation: J Muscle Res Cell Motil. 2004;25(8):645-55
references.pmid: 15750849
references.citation: Trends Cell Biol. 2006 Jan;16(1):36-44
references.pmid: 16325404
references.citation: Mol Cell Endocrinol. 2006 Jun 27;252(1-2):224-30
references.pmid: 16644098
references.citation: Biol Cell. 2002 Nov;94(7-8):535-43
references.pmid: 12566226
references.citation: Cell. 2007 Jun 1;129(5):999-1010
references.pmid: 17540178
references.citation: Cytogenet Cell Genet. 2000;90(1-2):71-4
references.pmid: 11060451
references.citation: Nature. 1991 Aug 8;352(6335):536-9
references.pmid: 1865908
references.citation: J Cell Sci. 2003 Jul 15;116(Pt 14):2885-93
references.pmid: 12771182
references.citation: Cell Mol Life Sci. 2013 Jan;70(2):223-37
references.pmid: 22695679