• Open Access

Nitric Oxide Sustains Long-Term Skeletal Muscle Regeneration by Regulating Fate of Satellite Cells Via Signaling Pathways Requiring Vangl2 and Cyclic GMP§

Authors

  • Roberta Buono,

    1. Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy
    2. Unit of Clinical Pharmacology, Consiglio Nazionale delle Ricerche Institute of Neuroscience, Department of Clinical Sciences L.Sacco, University Hospital “Luigi Sacco,” Università di Milano, Milan, Italy
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  • Chiara Vantaggiato,

    1. E. Medea Scientific Institute, Bosisio Parini, Lecco, Italy
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  • Viviana Pisa,

    1. Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy
    2. Unit of Clinical Pharmacology, Consiglio Nazionale delle Ricerche Institute of Neuroscience, Department of Clinical Sciences L.Sacco, University Hospital “Luigi Sacco,” Università di Milano, Milan, Italy
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  • Emanuele Azzoni,

    1. Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy
    2. Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy
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  • Maria Teresa Bassi,

    1. E. Medea Scientific Institute, Bosisio Parini, Lecco, Italy
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  • Silvia Brunelli,

    1. Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy
    2. Department of Experimental Medicine, University of Milano-Bicocca, Monza, Italy
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  • Clara Sciorati,

    Corresponding author
    1. Division of Regenerative Medicine, San Raffaele Scientific Institute, Milano, Italy
    • Division of Regenerative Medicine, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy
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    • Telephone: 39 02 26436342; Fax: + 39 02 26434813

  • Emilio Clementi

    Corresponding author
    1. Unit of Clinical Pharmacology, Consiglio Nazionale delle Ricerche Institute of Neuroscience, Department of Clinical Sciences L.Sacco, University Hospital “Luigi Sacco,” Università di Milano, Milan, Italy
    2. E. Medea Scientific Institute, Bosisio Parini, Lecco, Italy
    • Unit of Clinical Pharmacology, L. Sacco University Hospital, Via GB Grassi 74, 20157 Milano, Italy
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    • Telephone: 39 0250319686; Fax: 39 0250319646


  • Author contributions: R.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; C.V.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript, V.P. and E.A.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; M.T.B.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript; S.B.: conception and design, financial support, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript, C.S.: conception and design, administrative support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript, E.C.: conception and design, financial support, administrative support, provision of study material or patients, collection and/or assembly of data, data analysis and interpretation, manuscript writing, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS November 14, 2011.

  • Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms

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. STEM CELLS 2012; 30:197–209.

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