title: Fibroadipogenic progenitors mediate the ability of HDAC inhibitors to promote regeneration in dystrophic muscles of young, but not old Mdx mice.
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.
authors.affiliation: IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mozzetta
authors.forename: Silvia
authors.initials: S
authors.lastname: Consalvi
authors.forename: Valentina
authors.initials: V
authors.lastname: Saccone
authors.forename: Matthew
authors.initials: M
authors.lastname: Tierney
authors.forename: Adamo
authors.initials: A
authors.lastname: Diamantini
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Mitchell
authors.forename: Giovanna
authors.initials: G
authors.lastname: Marazzi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Borsellino
authors.forename: Luca
authors.initials: L
authors.lastname: Battistini
authors.forename: David
authors.initials: D
authors.lastname: Sassoon
authors.forename: Alessandra
authors.initials: A
authors.lastname: Sacco
authors.forename: Pier Lorenzo
authors.initials: PL
authors.lastname: Puri
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D016513:Mice, SCID; D009132:Muscles / Q000187:drug effects / Q000503:physiopathology*; D009136:Muscular Dystrophies / Q000188:drug therapy* / Q000503:physiopathology; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects
chemical_list: D056572:Histone Deacetylase Inhibitors