Duchenne muscular dystrophy (DMD) is a lethal X-linked neuromuscular disorder character-ized by progressive muscle degeneration due to lack of dystrophin, a protein essential for the integrity of sarcolemma during contraction. Chronic inflammation is a hallmark of muscles in DMD subjects, and contributes to progressive muscle wasting. RAGE (receptor for ad-vanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily involved in physiological and pathological processes including inflammation and myogenesis [1]. While absent in healthy adult muscle tissue, RAGE is expressed in regenerating myofi-bers during muscle regeneration [2,3], in dystrophic muscles and activated immune cells. To have information about the role of RAGE in the pathophysiology of DMD we generated a double mutant mouse lacking dystrophin and RAGE (mdx/Ager–/– mouse) by cross-breeding dystrophic (mdx) mice with RAGE-null (Ager-/-) mice. Comparison of quadriceps femoris of mdx and mdx/Ager–/– mice at different ages (i.e., 2, 3, 4 and 5 weeks, and 6 and 12 months of age) showed that the absence of RAGE in dystrophic mice did not affect the onset of the pathology. However, compared with age-matched mdx mice, muscles of 5 week- and 6 and 12 month-old mdx/Ager–/– mice showed i) significantly reduced numbers of necrotic myofi-bers, ii) a shift towards higher values of the cross-sectional areas (CSA) of myofibers, which was also evident in regenerating (centrally-nucleated) myofibers, and iii) reduced areas of immune cell infiltrate. The expression of MAC3, a marker of activated macrophages, was strongly reduced in muscles of mdx/Ager–/– mice compared with mdx mice. Moreover, mus-cles of mdx/Ager–/– mice exhibited significantly reduced PAX7+ve and myogenin+ve cell num-bers, suggesting a reduced recruitment of muscle precursor cells and more efficient regen-eration in dystrophic mice lacking RAGE. Our results suggest that RAGE may sustain in-flammatory and degenerative processes in dystrophic muscles, and the inhibition of its ex-pression/activity might represent a potential therapeutic approach in DMD patients. This work was supported by grants from MIUR 2012N8YJC3, AFM 16812 and Fonda-zione CRP 2015.0325.021. References [1] Sorci G. et al. (2004) Mol. Cell. Biol. 24:4880-94 [2] Riuzzi F. et al. (2012) J. Cell Sci. 125:1440-54 [3] Haslbeck K.M. et al. (2005) Acta Neuropathol. 110:247-54

Absence of RAGE in an animal experimental model of Duchenne muscular dystrophy results in reduced muscle necrosis and inflammation

Roberta Sagheddu;Sara Chiappalupi;Laura Salvadori;Francesca Riuzzi;Guglielmo Sorci;Rosario Donato
2016

Abstract

Duchenne muscular dystrophy (DMD) is a lethal X-linked neuromuscular disorder character-ized by progressive muscle degeneration due to lack of dystrophin, a protein essential for the integrity of sarcolemma during contraction. Chronic inflammation is a hallmark of muscles in DMD subjects, and contributes to progressive muscle wasting. RAGE (receptor for ad-vanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily involved in physiological and pathological processes including inflammation and myogenesis [1]. While absent in healthy adult muscle tissue, RAGE is expressed in regenerating myofi-bers during muscle regeneration [2,3], in dystrophic muscles and activated immune cells. To have information about the role of RAGE in the pathophysiology of DMD we generated a double mutant mouse lacking dystrophin and RAGE (mdx/Ager–/– mouse) by cross-breeding dystrophic (mdx) mice with RAGE-null (Ager-/-) mice. Comparison of quadriceps femoris of mdx and mdx/Ager–/– mice at different ages (i.e., 2, 3, 4 and 5 weeks, and 6 and 12 months of age) showed that the absence of RAGE in dystrophic mice did not affect the onset of the pathology. However, compared with age-matched mdx mice, muscles of 5 week- and 6 and 12 month-old mdx/Ager–/– mice showed i) significantly reduced numbers of necrotic myofi-bers, ii) a shift towards higher values of the cross-sectional areas (CSA) of myofibers, which was also evident in regenerating (centrally-nucleated) myofibers, and iii) reduced areas of immune cell infiltrate. The expression of MAC3, a marker of activated macrophages, was strongly reduced in muscles of mdx/Ager–/– mice compared with mdx mice. Moreover, mus-cles of mdx/Ager–/– mice exhibited significantly reduced PAX7+ve and myogenin+ve cell num-bers, suggesting a reduced recruitment of muscle precursor cells and more efficient regen-eration in dystrophic mice lacking RAGE. Our results suggest that RAGE may sustain in-flammatory and degenerative processes in dystrophic muscles, and the inhibition of its ex-pression/activity might represent a potential therapeutic approach in DMD patients. This work was supported by grants from MIUR 2012N8YJC3, AFM 16812 and Fonda-zione CRP 2015.0325.021. References [1] Sorci G. et al. (2004) Mol. Cell. Biol. 24:4880-94 [2] Riuzzi F. et al. (2012) J. Cell Sci. 125:1440-54 [3] Haslbeck K.M. et al. (2005) Acta Neuropathol. 110:247-54
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1477346
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