Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice

EMBO Molecular Medicine

Chiara Mozzetta³  Silvia Consalvi³  Valentina Saccone³  Matthew Tierney¹  Adamo Diamantini³  Kathryn J. Mitchell²  Giovanna Marazzi²  Giovanna Borsellino³  Luca Battistini³  David Sassoon²  Alessandra Sacco¹ 

[1] Sanford-Burnham Medical Research Institute, Sanford Children's Health Research Center, La Jolla, CA, USA;Myology Group, UMR S 787 INSERM, Université Pierre et Marie Curie Paris VI, Paris, France;IRCCS Fondazione Santa Lucia, Rome, Italy

关键词: fibroadipogenic progenitors;    HDAC inhibitors;    muscle regeneration;    muscle stem cells;    muscular dystrophy;   

DOI  :  10.1002/emmm.201202096

来源: Wiley

【 摘 要 】

Abstract

HDAC inhibitors (HDACi) exert beneficial effects in mdx mice, by promoting endogenous regeneration; however, the cellular determinants of HDACi activity on dystrophic muscles have not been determined. We show that fibroadipogenic progenitors (FAP) influence the regeneration potential of satellite cells during disease progression in mdx mice and mediate HDACi ability to selectively promote regeneration at early stages of disease. FAPs from young mdx mice promote, while FAPs from old mdx mice repress, satellite cell-mediated formation of myotubes. In young mdx mice HDACi inhibited FAP adipogenic potential, while enhancing their ability to promote differentiation of adjacent satellite cells, through upregulation of the soluble factor follistatin. By contrast, FAPs from old mdx mice were resistant to HDACi-mediated inhibition of adipogenesis and constitutively repressed satellite cell-mediated formation of myotubes. We show that transplantation of FAPs from regenerating young muscles restored HDACi ability to increase myofibre size in old mdx mice. These results reveal that FAPs are key cellular determinants of disease progression in mdx mice and mediate a previously unappreciated stage-specific beneficial effect of HDACi in dystrophic muscles.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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