Year-end Sale % OFF 
Abstract
Various therapeutic approaches have been studied for the treatment of Duchenne muscular dystrophy (DMD), but none of these approaches have led to significant long-term effects in patients. One reason for this observed inefficacy may be the use of inappropriate animal models for the testing of therapeutic agents. The mdx mouse is the most widely used murine model of DMD, yet it does not model the fibrotic progression observed in patients. Other murine models of DMD are available that lack one or both alleles of utrophin, a functional analog of dystrophin. The aim of this study was to compare fibrosis and myofiber damage in the mdx, mdx/utrn+/- and double knockout (dko) mouse models. We used Masson’s trichrome stain and percentage of centrally-nucleated myofibers as indicators of fibrosis and myofiber regeneration, respectively, to assess disease progression in diaphragm and gastrocnemius muscles harvested from young and aged wild-type, mdx, mdx/utrn+/- and dko mice. Our results indicated that eight week-old gastrocnemius muscles of both mdx/utrn+/- and dko hind limb developed fibrosis whereas age-matched mdx gastrocnemius muscle did not (p = 0.002). The amount of collagen found in the mdx/utrn+/- diaphragm was significantly higher than that found in the corresponding diaphragm muscles of wild-type animals, but not of mdx animals (p = 0.0003). Aged mdx/utrn+/- mice developed fibrosis in both diaphragm and gastrocnemius muscles compared to wild-type controls (p = 0.003). Mdx diaphragm was fibrotic in aged mice as well (p = 0.0235), whereas the gastrocnemius muscle in these animals was not fibrotic. We did not measure a significant difference in collagen staining between wild-type and mdx gastrocnemius muscles. The results of this study support previous reports that the moderately-affected mdx/utrn+/- mouse is a better model of DMD, and we show here that this difference is apparent by 2 months of age.
Highlights
Treatment strategies for Duchenne muscular dystrophy (DMD), a severe neuromuscular degenerative disorder, have been ongoing for decades with little significant long-term efficacy reported [1]
We examine extent of fibrosis and muscle regeneration in 8 week-old mice as well as aged 10 month-old mice and provide a comprehensive analysis of these parameters in various skeletal muscles that are used in DMD research
Fibrosis is present at ten months of age in mdx/utrn+/, but not mdx, gastrocnemius muscle
Summary
Treatment strategies for Duchenne muscular dystrophy (DMD), a severe neuromuscular degenerative disorder, have been ongoing for decades with little significant long-term efficacy reported [1]. A number of studies in DMD patients have used cell therapy to replace dystrophin, reporting an increase in dystrophin-positive myofibers [2,3,4,5,6,7,8] While these studies have successfully reintroduced the protein to dystrophic skeletal muscle, improvements in function have been limited. A single treatment was sufficient to restore dystrophin in all muscles examined, including heart tissue, and dramatically increased life expectancy from 10 to 50 weeks of age [18] These studies have been crucial in highlighting the need for inclusion of a more accurate DMD mouse model with which to assess the efficacy of therapeutic strategies
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
