Negroni Elisa, Henault Emilie, Chevalier Fabien, Gilbert-Sirieix Marie, Van Kuppevelt Toin H, Papy-Garcia Dulce, Uzan Georges, Albanese Patricia
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).
J Neuropathol Exp Neurol. 2014 Aug;73(8):789-97. doi: 10.1097/NEN.0000000000000098.
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.
杜兴氏肌营养不良症（DMD）患者中广泛的骨骼肌退化和再生受损会导致进行性肌肉无力和过早死亡。由于肌肉前体细胞耗尽和细胞外基质（ECM）过度积累，营养不良的肌肉逐渐被无功能组织取代。硫酸化糖胺聚糖（GAGs）是ECM的组成部分，越来越多地参与生物过程的调节，但其在DMD病理进展中的可能作用尚不清楚。在本研究中，我们对10名DMD患者和11名健康个体（对照）的骨骼肌活检组织中的内源性GAGs进行了免疫组织化学和生化分析。针对特定GAG种类的免疫染色显示，与对照活检相比，DMD患者活检组织中硫酸软骨素（CS）/硫酸皮肤素（DS）的沉积更多。通过生化定量分析证实了DMD活检组织中CS/DS的选择性积累。此外，高效液相色谱分析表明DMD肌肉中CS/DS二糖单位的硫酸化模式发生了改变。总之，我们的数据开辟了一条新的研究途径，并表明GAGs可能代表一种新的、原创的治疗靶点，以提高基因或细胞治疗肌肉营养不良症的成功率。
