Gene-mediated restoration of normal myofiber elasticity in dystrophic muscles

Stefania Puttini, Małgorzata Lekka, Olivier M. Dorchies, Damien Saugy, Tania Incitti, Urs T. Ruegg, Irene Bozzoni, Andrzej J. Kulik, Nicolas Mermod

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37 Scopus citations

Abstract

Dystrophin mediates a physical link between the cytoskeleton of muscle fibers and the extracellular matrix, and its absence leads to muscle degeneration and dystrophy. In this article, we show that the lack of dystrophin affects the elasticity of individual fibers within muscle tissue explants, as probed using atomic force microscopy (AFM), providing a sensitive and quantitative description of the properties of normal and dystrophic myofibers. The rescue of dystrophin expression by exon skipping or by the ectopic expression of the utrophin analogue normalized the elasticity of dystrophic muscles, and these effects were commensurate to the functional recovery of whole muscle strength. However, a more homogeneous and widespread restoration of normal elasticity was obtained by the exon-skipping approach when comparing individual myofibers. AFM may thus provide a quantification of the functional benefit of gene therapies from live tissues coupled to single-cell resolution.

Original languageEnglish (US)
Pages (from-to)19-25
Number of pages7
JournalMolecular Therapy
Volume17
Issue number1
DOIs
StatePublished - 2009

Bibliographical note

Funding Information:
We are grateful to ParkSystems for the free loan of an XE 120 AFM system, to A. Khan, R. Draghia-Akli, and VGX Pharmaceuticals for help with in vivo electroporation, to A. Briguet and T. Meyer for the gift of plasmids, and to O. Patthey-Vuadens for expert immunofluorescence studies. This work was supported by grants from the Swiss Foundation for Research on Muscle Diseases to N.M. and U.T.R., the European CLINIGENE Network of Excellence (N.M.), the Swiss National Science Foundation (U.T.R.), the Telethon and Duchenne Parent Project Italia (I.B.), the Universities of Lausanne and Geneva, and the Institute Pasteur Cenci-Bolognetti.

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