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Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal.

Pigozzo SR, Da Re L, Romualdi C, Mazzara PG, Galletta E, Fletcher S, Wilton SD, Vitiello L - PLoS ONE (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

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Related in: MedlinePlus

Interaction between the number of isolated RFs and the age of the animals.Chart is organized as in Figure 1B; for each muscle, values were obtained by averaging the absolute number of single dystrophin-positive fibers (i.e., separated by at least two negative fibers from neighboring RFs) found in each section.
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pone-0072147-g003: Interaction between the number of isolated RFs and the age of the animals.Chart is organized as in Figure 1B; for each muscle, values were obtained by averaging the absolute number of single dystrophin-positive fibers (i.e., separated by at least two negative fibers from neighboring RFs) found in each section.

Mentions: As shown in Figure 3, when comparing the different age groups two distinct trends could be seen. For some muscles (EDL, plantaris, soleus and intercostal), the average number of isolated fibers per section remained essentially constant at all time points, whereas for all other muscles there was a distinct increase with ageing. In particular, the difference between groups 1 and 2 was significant (p<0.001) in tibialis anterior, gastrocnemius and triceps; between groups 1 and 3 in tibialis, gastrocnemius, quadriceps, diaphragm and triceps; between groups 2 and 3 in quadriceps and diaphragm; between groups 2 and 4 in tibialis anterior, quadriceps, diaphragm, chest and triceps. Finally, the difference between groups 1 and 4 was significant in all muscles except EDL, soleus and plantaris.


Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal.

Pigozzo SR, Da Re L, Romualdi C, Mazzara PG, Galletta E, Fletcher S, Wilton SD, Vitiello L - PLoS ONE (2013)

Interaction between the number of isolated RFs and the age of the animals.Chart is organized as in Figure 1B; for each muscle, values were obtained by averaging the absolute number of single dystrophin-positive fibers (i.e., separated by at least two negative fibers from neighboring RFs) found in each section.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756063&req=5

pone-0072147-g003: Interaction between the number of isolated RFs and the age of the animals.Chart is organized as in Figure 1B; for each muscle, values were obtained by averaging the absolute number of single dystrophin-positive fibers (i.e., separated by at least two negative fibers from neighboring RFs) found in each section.
Mentions: As shown in Figure 3, when comparing the different age groups two distinct trends could be seen. For some muscles (EDL, plantaris, soleus and intercostal), the average number of isolated fibers per section remained essentially constant at all time points, whereas for all other muscles there was a distinct increase with ageing. In particular, the difference between groups 1 and 2 was significant (p<0.001) in tibialis anterior, gastrocnemius and triceps; between groups 1 and 3 in tibialis, gastrocnemius, quadriceps, diaphragm and triceps; between groups 2 and 3 in quadriceps and diaphragm; between groups 2 and 4 in tibialis anterior, quadriceps, diaphragm, chest and triceps. Finally, the difference between groups 1 and 4 was significant in all muscles except EDL, soleus and plantaris.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus