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.
Highlights
Duchenne muscular dystrophy (DMD, OMIM #310200) is the most common X-linked recessive disease, with an incidence of approximately 1 every 3500 newborn males
The presence of revertant fibers has no effect on the clinical phenotype; dystrophin expression is limited to few nuclear domains, with a longitudinal extension spanning 100 to 300 mm [6], and such ‘‘patchy’’ distribution cannot protect revertant fibers’’ (RFs) from sarcolemmal damage [6,9]
Cardiac muscle had the lowest number of revertant cardiomyocytes, 0.6/mm2
Summary
Duchenne muscular dystrophy (DMD, OMIM #310200) is the most common X-linked recessive disease, with an incidence of approximately 1 every 3500 newborn males. Even in the presence of frameshifting deletions of tens to hundreds of kilobases within the dystrophin gene, occasional dystrophin-positive ‘‘revertant fibers’’ (RFs) can be found in about 50% of DMD patients, in whom they can account for up to 7% of the total [1,2,3,4,5,6,7,8,9]. The presence of revertant fibers has no effect on the clinical phenotype; dystrophin expression is limited to few nuclear domains, with a longitudinal extension spanning 100 to 300 mm (but occasionally up to 900 mm) [6], and such ‘‘patchy’’ distribution cannot protect RFs from sarcolemmal damage [6,9]
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