title: Inhibition of muscle fibrosis results in increases in both utrophin levels and the number of revertant myofibers in Duchenne muscular dystrophy.
abstract: Duchenne Muscular Dystrophy is characterized by: near absence of dystrophin in skeletal muscles; low percentage of revertant myofibers; up-regulation of utrophin synthesis; and a high degree of muscle fibrosis. In patient quadriceps femoris biopsies (n = 6, ages between 3-9 years) an inverse correlation was observed between the levels of collagen type I - representing fibrosis - and the levels of utrophin. This correlation was independent of the patient's age and was observed in the entire muscle biopsy sections. In the mdx mice diaphragm (n = 6/group), inhibition of fibrosis by halofuginone resulted in increases in the levels of utrophin. The utrophin/fibrosis relationships were not limited to collagen type I, but also applied to other constituents of the fibrosis machinery. The inverse correlation was found also in old mdx mice with established fibrosis. In addition, inhibition of collagen type I levels was associated with increases in the numbers of revertant myofibers, both as single myofibers and in clusters in the diaphragm and the gastrocnemius. In summary, our results demonstrate an inverse correlation between the level of muscle fibrosis and the level of utrophin and that of the number of revertant myofibers. These findings may reveal common links between the fibrotic and utrophin-synthesis pathways and offer new insights into the regulation of utrophin synthesis.
authors.affiliation: Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Levi
authors.affiliation: Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
authors.forename: Olga
authors.initials: O
authors.lastname: Genin
authors.affiliation: Department of Neurosciences, University of Padova and IRCCS S. Camillo, Lido, Venice, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Angelini
authors.affiliation: Department of Animal Sciences, the Hebrew University of Jerusalem, Rehovot, Israel.
authors.forename: Orna
authors.initials: O
authors.lastname: Halevy
authors.affiliation: Institute of Animal Sciences, Volcani Center, Bet Dagan, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Pines
mesh_terms: D000818:Animals; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology*; D010880:Piperidines / Q000737:chemistry; D052097:Quadriceps Muscle / Q000378:metabolism / Q000473:pathology; D052999:Quinazolinones / Q000737:chemistry; D049411:Utrophin / Q000378:metabolism*
chemical_list: D024042:Collagen Type I; D010880:Piperidines; D052999:Quinazolinones; D049411:Utrophin; D003094:Collagen; C010176:halofuginone
keywords: Pathology Section; collagen; fibrosis; halofuginone; muscular dystrophy; utrophin