Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology affecting 1:5000 male birth and characterized by progressive muscle degeneration due to lack of dystrophin, a protein crucial for the stabilization of myofiber sarcolemma during contraction [1]. Muscles of DMD patients are characterized by chronic inflammation, which plays a major role in the progression of the pathology. RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily involved in physiological and pathological processes including inflammation and myogenesis [2]. Whereas RAGE is not expressed in adult muscle tissue, it is expressed in immune cells, regenerating myofibers during muscle regeneration, and dystrophic muscle tissue. The mdx mouse represents the best characterized animal model of DMD. To have information about the role of RAGE in the pathophysiology of DMD we generated a double mutant mdx/Ager–/– mouse lacking both dystrophin and RAGE. We analyzed diaphragms and hind-limb muscles of 4-week-old mdx/Ager–/– mice in comparison with those of age-matched mdx mice, since this age corresponds to the acute phase of the pathology in the mdx model. Haematoxylin/eosin analysis revealed significantly reduced numbers of necrotic myofibers, reduced areas of immune cell infiltrate, and similar percentages of centrally-nucleated myofibers in muscles of mdx/Ager–/– mice compared with mdx mice. Moreover, mdx/Ager–/– muscles showed strongly reduced MAC3 areas and reduced MAC3 expression as analyzed by immunohistochemistry and Western blotting, respectively. These preliminary results suggest that RAGE might have a role in the progression of DMD pathology. 1. D.J. Blake, A. Weir, S.E. Newey, K.E. Davies. (2002) Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol. Rev. 82, 291-329 2. G.P. Sims, D.C. Rowe, S.T. Rietdijk, R. Herbst, A.J. Coyle. (2010) HMGB1 and RAGE in Inflammation and Cancer. Annu. Rev. Immunol. 28:367-388
Generation of an mdx/Ager–/– double mutant mouse. Preliminary data on skeletal muscle architecture.
CHIAPPALUPI, SARA;SALVADORI, LAURA;DONATO, Rosario Francesco;SORCI, Guglielmo
2014
Abstract
Duchenne muscular dystrophy (DMD) is a lethal X-linked pathology affecting 1:5000 male birth and characterized by progressive muscle degeneration due to lack of dystrophin, a protein crucial for the stabilization of myofiber sarcolemma during contraction [1]. Muscles of DMD patients are characterized by chronic inflammation, which plays a major role in the progression of the pathology. RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily involved in physiological and pathological processes including inflammation and myogenesis [2]. Whereas RAGE is not expressed in adult muscle tissue, it is expressed in immune cells, regenerating myofibers during muscle regeneration, and dystrophic muscle tissue. The mdx mouse represents the best characterized animal model of DMD. To have information about the role of RAGE in the pathophysiology of DMD we generated a double mutant mdx/Ager–/– mouse lacking both dystrophin and RAGE. We analyzed diaphragms and hind-limb muscles of 4-week-old mdx/Ager–/– mice in comparison with those of age-matched mdx mice, since this age corresponds to the acute phase of the pathology in the mdx model. Haematoxylin/eosin analysis revealed significantly reduced numbers of necrotic myofibers, reduced areas of immune cell infiltrate, and similar percentages of centrally-nucleated myofibers in muscles of mdx/Ager–/– mice compared with mdx mice. Moreover, mdx/Ager–/– muscles showed strongly reduced MAC3 areas and reduced MAC3 expression as analyzed by immunohistochemistry and Western blotting, respectively. These preliminary results suggest that RAGE might have a role in the progression of DMD pathology. 1. D.J. Blake, A. Weir, S.E. Newey, K.E. Davies. (2002) Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol. Rev. 82, 291-329 2. G.P. Sims, D.C. Rowe, S.T. Rietdijk, R. Herbst, A.J. Coyle. (2010) HMGB1 and RAGE in Inflammation and Cancer. Annu. Rev. Immunol. 28:367-388I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
