title: Glycosaminoglycan modifications in Duchenne muscular dystrophy: specific remodeling of chondroitin sulfate/dermatan sulfate.
abstract: Widespread skeletal muscle degeneration and impaired regeneration lead to progressive muscle weakness and premature death in patients with Duchenne muscular dystrophy (DMD). Dystrophic muscles are progressively replaced by nonfunctional tissue because of exhaustion of muscle precursor cells and excessive accumulation of extracellular matrix (ECM). Sulfated glycosaminoglycans (GAGs) are components of the ECM and are increasingly implicated in the regulation of biologic processes, but their possible role in the progression of DMD pathology is not understood. In the present study, we performed immunohistochemical and biochemical analyses of endogenous GAGs in skeletal muscle biopsies of 10 DMD patients and 11 healthy individuals (controls). Immunostaining targeted to specific GAG species showed greater deposition of chondroitin sulfate (CS)/dermatan (DS) sulfate in DMD patient biopsies versus control biopsies. The selective accumulation of CS/DS in DMD biopsies was confirmed by biochemical quantification assay. In addition, high-performance liquid chromatography analysis demonstrated a modification of the sulfation pattern of CS/DS disaccharide units in DMD muscles. In conclusion, our data open up a new path of investigation and suggest that GAGs could represent a new and original therapeutic target for improving the success of gene or cell therapy for the treatment of muscular dystrophies.
authors.affiliation: From the INSERM U972, Paul Brousse Hospital, Villejuif (EN, FC, GU); and EAC CNRS 7149, CRRET Laboratory, Sciences and Technology Faculty, Paris-Est Creteil University, Créteil (EH, FC, MG-S, DP-G, PA), France; and Department of Biochemistry (280), Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands (THVK).
authors.forename: Elisa
authors.initials: E
authors.lastname: Negroni
authors.forename: Emilie
authors.initials: E
authors.lastname: Henault
authors.forename: Fabien
authors.initials: F
authors.lastname: Chevalier
authors.forename: Marie
authors.initials: M
authors.lastname: Gilbert-Sirieix
authors.forename: Toin H
authors.initials: TH
authors.lastname: Van Kuppevelt
authors.forename: Dulce
authors.initials: D
authors.lastname: Papy-Garcia
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
authors.forename: Patricia
authors.initials: P
authors.lastname: Albanese
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002809:Chondroitin Sulfates / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003871:Dermatan Sulfate / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006025:Glycosaminoglycans / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D055815:Young Adult
chemical_list: D006025:Glycosaminoglycans; D012333:RNA, Messenger; C069524:dermatan sulfate chondroitin sulfate; D003871:Dermatan Sulfate; D002809:Chondroitin Sulfates