title: Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal.
abstract: Muscles in Duchenne dystrophy patients are characterized by the absence of dystrophin, yet transverse sections show a small percentage of fibers (termed "revertant fibers") positive for dystrophin expression. This phenomenon, whose biological bases have not been fully elucidated, is present also in the murine and canine models of DMD and can confound the evaluation of therapeutic approaches. We analyzed 11 different muscles in a cohort of 40 mdx mice, the most commonly model used in pre-clinical studies, belonging to four age groups; such number of animals allowed us to perform solid ANOVA statistical analysis. We assessed the average number of dystrophin-positive fibers, both absolute and normalized for muscle size, and the correlation between their formation and the ageing process. Our results indicate that various muscles develop different numbers of revertant fibers, with different time trends; besides, they suggest that the biological mechanism(s) behind dystrophin re-expression might not be limited to the early development phases but could actually continue during adulthood. Importantly, such finding was seen also in cardiac muscle, a fact that does not fit into the current hypothesis of the clonal origin of "revertant" myonuclei from satellite cells. This work represents the largest, statistically significant analysis of revertant fibers in mdx mice so far, which can now be used as a reference point for improving the evaluation of therapeutic approaches for DMD. At the same time, it provides new clues about the formation of revertant fibers/cardiomyocytes in dystrophic skeletal and cardiac muscle.
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, University of Western Australia Queen Elizabeth II Medical Centre, Nedlands Western Australia, Australia ; Department of Biology, University of Padova, Padova, Italy.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Pigozzo
authors.forename: Lorena
authors.initials: L
authors.lastname: Da Re
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
authors.forename: Pietro G
authors.initials: PG
authors.lastname: Mazzara
authors.forename: Eva
authors.initials: E
authors.lastname: Galletta
authors.forename: Sue
authors.initials: S
authors.lastname: Fletcher
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wilton
authors.forename: Libero
authors.initials: L
authors.lastname: Vitiello
mesh_terms: D000367:Age Factors; D000818:Animals; D016189:Dystrophin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology*; D018482:Muscle, Skeletal / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology
chemical_list: D016189:Dystrophin