title: Nitric oxide sustains long-term skeletal muscle regeneration by regulating fate of satellite cells via signaling pathways requiring Vangl2 and cyclic GMP.
abstract: Satellite cells are myogenic precursors that proliferate, activate, and differentiate on muscle injury to sustain the regenerative capacity of adult skeletal muscle; in this process, they self-renew through the return to quiescence of the cycling progeny. This mechanism, while efficient in physiological conditions does not prevent exhaustion of satellite cells in pathologies such as muscular dystrophy where numerous rounds of damage occur. Here, we describe a key role of nitric oxide, an important signaling molecule in adult skeletal muscle, on satellite cells maintenance, studied ex vivo on isolated myofibers and in vivo using the α-sarcoglycan null mouse model of dystrophy and a cardiotoxin-induced model of repetitive damage. Nitric oxide stimulated satellite cells proliferation in a pathway dependent on cGMP generation. Furthermore, it increased the number of Pax7(+)/Myf5(-) cells in a cGMP-independent pathway requiring enhanced expression of Vangl2, a member of the planar cell polarity pathway involved in the Wnt noncanonical pathway. The enhanced self-renewal ability of satellite cells induced by nitric oxide is sufficient to delay the reduction of the satellite cell pool during repetitive acute and chronic damages, favoring muscle regeneration; in the α-sarcoglycan null dystrophic mouse, it also slowed disease progression persistently. These results identify nitric oxide as a key messenger in satellite cells maintenance, expand the significance of the Vangl2-dependent Wnt noncanonical pathway in myogenesis, and indicate novel strategies to optimize nitric oxide-based therapies for muscular dystrophy.
authors.affiliation: Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Buono
authors.forename: Chiara
authors.initials: C
authors.lastname: Vantaggiato
authors.forename: Viviana
authors.initials: V
authors.lastname: Pisa
authors.forename: Emanuele
authors.initials: E
authors.lastname: Azzoni
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bassi
authors.forename: Silvia
authors.initials: S
authors.lastname: Brunelli
authors.forename: Clara
authors.initials: C
authors.lastname: Sciorati
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D057507:Mice, 129 Strain; D008981:Molsidomine / Q000494:pharmacology / Q000627:therapeutic use; D024510:Muscle Development / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000196:embryology / Q000502:physiology*; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology / Q000627:therapeutic use; D012038:Regeneration; D032496:Satellite Cells, Skeletal Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
chemical_list: C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D008981:Molsidomine; D006152:Cyclic GMP
references.citation: FASEB J. 2006 Apr;20(6):738-40
references.pmid: 16464957
references.citation: Brain Dev. 2000 May;22(3):181-3
references.pmid: 10814901
references.citation: J Cell Sci. 2008 Sep 15;121(Pt 18):2975-82
references.pmid: 18768931
references.citation: J Exp Med. 1996 Aug 1;184(2):609-18
references.pmid: 8760814
references.citation: Dis Model Mech. 2009 Jul-Aug;2(7-8):374-88
references.pmid: 19535499
references.citation: Biochim Biophys Acta. 2010 Dec;1802(12):1276-84
references.pmid: 20460153
references.citation: Cell Cycle. 2007 Dec 15;6(24):3132-44
references.pmid: 18073535
references.citation: Science. 2003 Jul 25;301(5632):487-92
references.pmid: 12855815
references.citation: J Cell Sci. 2006 Dec 15;119(Pt 24):5114-23
references.pmid: 17158915
references.citation: Cell Res. 2011 Nov;21(11):1591-604
references.pmid: 21502976
references.citation: Cell Stem Cell. 2008 Jan 10;2(1):22-31
references.pmid: 18371418
references.citation: Clin Exp Pharmacol Physiol. 2008 Dec;35(12):1488-92
references.pmid: 18759853
references.citation: J Clin Invest. 2010 Jan;120(1):11-9
references.pmid: 20051632
references.citation: EMBO J. 1999 Dec 15;18(24):6867-72
references.pmid: 10601008
references.citation: Nitric Oxide. 2009 Nov-Dec;21(3-4):157-63
references.pmid: 19682596
references.citation: J Cell Sci. 2008 May 1;121(Pt 9):1373-82
references.pmid: 18397993
references.citation: Lancet. 2002 Feb 23;359(9307):687-95
references.pmid: 11879882
references.citation: Am J Physiol Cell Physiol. 2006 Jun;290(6):C1487-94
references.pmid: 16684931
references.citation: J Cell Biol. 1998 Sep 21;142(6):1461-71
references.pmid: 9744877
references.citation: Circ Res. 2007 Mar 30;100(6):795-806
references.pmid: 17395885
references.citation: Hum Mol Genet. 2010 Nov 1;19(21):4145-59
references.pmid: 20705734
references.citation: Nature. 2006 Nov 30;444(7119):574-9
references.pmid: 17108972
references.citation: Stem Cells. 2007 Oct;25(10):2448-59
references.pmid: 17600112
references.citation: Am J Med Genet A. 2005 Jul 1;136(1):90-2
references.pmid: 15952208
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):264-9
references.pmid: 17182743
references.citation: Lancet. 2011 Aug 13;378(9791):595-605
references.pmid: 21784508
references.citation: Mol Ther. 2011 May;19(5):830-40
references.pmid: 21468001
references.citation: Am J Physiol Cell Physiol. 2010 Mar;298(3):C465-76
references.pmid: 20007454
references.citation: Curr Opin Cell Biol. 2009 Dec;21(6):748-53
references.pmid: 19932015
references.citation: Gene Expr Patterns. 2003 Dec;3(6):755-9
references.pmid: 14643684
references.citation: Mol Biol Cell. 2000 May;11(5):1859-74
references.pmid: 10793157
references.citation: Cell. 2005 Jul 29;122(2):289-301
references.pmid: 16051152
references.citation: Science. 2007 Aug 10;317(5839):807-10
references.pmid: 17690295
references.citation: Cell Cycle. 2003 Sep-Oct;2(5):418-9
references.pmid: 12963830
references.citation: J Cell Sci. 2008 Sep 1;121(Pt 17):2939-50
references.pmid: 18697834
references.citation: Cell Stem Cell. 2009 Jun 5;4(6):535-47
references.pmid: 19497282
references.citation: Exp Cell Res. 2008 Jan 15;314(2):317-29
references.pmid: 17949710
references.citation: Front Biosci. 2005 May 01;10:1239-68
references.pmid: 15769622
references.citation: J Biol Chem. 2009 Jul 31;284(31):20629-37
references.pmid: 19520846
references.citation: N Engl J Med. 2011 Apr 21;364(16):1513-22
references.pmid: 21428760
references.citation: J Cell Sci. 2006 May 1;119(Pt 9):1824-32
references.pmid: 16608873
references.citation: Cell Stem Cell. 2010 Feb 5;6(2):117-29
references.pmid: 20144785
references.citation: Neurobiol Dis. 2005 Oct;20(1):123-30
references.pmid: 16137573
references.citation: Neurochem Res. 2007 Apr-May;32(4-5):681-94
references.pmid: 17043768
references.citation: Dev Biol. 2007 Apr 15;304(2):604-14
references.pmid: 17275805
references.citation: Cell Stem Cell. 2009 Sep 4;5(3):298-309
references.pmid: 19733541
references.citation: J Cell Biol. 2007 Oct 22;179(2):305-19
references.pmid: 17954612
references.citation: Cell Death Differ. 2010 Nov;17(11):1684-96
references.pmid: 20467441
references.citation: J Cardiovasc Pharmacol. 1989;14 Suppl 11:S13-22
references.pmid: 2484692
references.citation: Cochrane Database Syst Rev. 2004;(2):CD003725
references.pmid: 15106215
references.citation: J Cell Biol. 1994 Jun;125(6):1275-87
references.pmid: 8207057
references.citation: Curr Opin Pharmacol. 2006 Jun;6(3):301-6
references.pmid: 16563862
references.citation: Cell Metab. 2011 Feb 2;13(2):149-59
references.pmid: 21284982
references.citation: Cell Stem Cell. 2008 Jan 10;2(1):50-9
references.pmid: 18371421
references.citation: Circ Res. 2005 Feb 18;96(3):292-9
references.pmid: 15637299
references.citation: Rejuvenation Res. 2011 Jun;14(3):249-60
references.pmid: 21453013
references.citation: Anat Embryol (Berl). 2006 Dec;211 Suppl 1:51-6
references.pmid: 17039375
references.citation: Curr Top Dev Biol. 2011;96:139-65
references.pmid: 21621070
references.citation: Muscle Nerve. 1981 May-Jun;4(3):204-13
references.pmid: 7242559
references.citation: In Vitro Cell Dev Biol Anim. 1995 Nov;31(10):773-9
references.pmid: 8564066
references.citation: PLoS One. 2010 Nov 29;5(11):e15055
references.pmid: 21124733
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19183-7
references.pmid: 19047631
references.citation: Hum Mol Genet. 2009 Sep 15;18(18):3439-51
references.pmid: 19542095
references.citation: FASEB J. 2002 Nov;16(13):1786-91
references.pmid: 12409321
references.citation: J Biol Chem. 2004 Dec 10;279(50):52703-13
references.pmid: 15456783
references.citation: J Histochem Cytochem. 2006 Nov;54(11):1177-91
references.pmid: 16899758
references.citation: Br J Pharmacol. 2010 Jul;160(6):1550-60
references.pmid: 20590643
references.citation: C R Biol. 2007 Jun-Jul;330(6-7):530-3
references.pmid: 17631448
references.citation: J Cell Biol. 2006 Jan 16;172(2):233-44
references.pmid: 16401724
references.citation: J Appl Physiol (1985). 2010 Jul;109(1):135-48
references.pmid: 20466802
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14022-4
references.pmid: 11121010
references.citation: J Cell Biol. 2001 Oct 1;155(1):123-31
references.pmid: 11581289
references.citation: Curr Opin Clin Nutr Metab Care. 2006 May;9(3):214-9
references.pmid: 16607119
references.citation: Dev Biol. 2009 Nov 1;335(1):93-105
references.pmid: 19699733
references.citation: Semin Cell Dev Biol. 2005 Aug-Oct;16(4-5):575-84
references.pmid: 16095933
references.citation: Cell. 1995 Sep 8;82(5):743-52
references.pmid: 7545544
references.citation: J Cell Biol. 2010 Aug 9;190(3):427-41
references.pmid: 20696709
references.citation: Microsc Res Tech. 2001 Nov 1;55(3):181-6
references.pmid: 11747093
references.citation: Heart Fail Rev. 2007 Dec;12(3-4):181-8
references.pmid: 17516169
references.citation: Pharmacol Res. 2011 Sep;64(3):210-7
references.pmid: 21609764
references.citation: Muscle Nerve. 2008 Feb;37(2):203-9
references.pmid: 18004769
references.citation: Cell. 2007 Jun 1;129(5):999-1010
references.pmid: 17540178
references.citation: Front Biosci. 2006 Jan 01;11:356-67
references.pmid: 16146737
references.citation: Physiol Rev. 2001 Jan;81(1):209-237
references.pmid: 11152758
references.citation: Am J Physiol Cell Physiol. 2008 Apr;294(4):C1088-95
references.pmid: 18272817