Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration due to lack of dystrophin, a protein essential for the integrity of sarcolemma during contraction. In DMD compensative degeneration/regeneration cycles determine a condition of chronic inflammation contributing to progressive muscle wasting. RAGE (receptor for advanced glycation end-products) is a multiligand receptor belonging to the immunoglobulin superfamily involved in physiological and pathological processes including inflammation and myogenesis [1]. RAGE is not expressed in adult muscle tissue, whereas it is expressed in regenerating myofibers 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 mdx/Ager–/– mouse lacking dystrophin and RAGE (Ager). We analyzed diaphragms and hind-limb muscles (i.e., tibialis anterior and quadriceps femoris) of mdx, mdx/Ager–/–, Ager–/– and WT mice at different ages (i.e., 2, 3, 4 and 5 weeks, and 3 and 6 months of age). We found that although the absence of RAGE in dystrophic mice did not affect the onset of the pathology, muscles of 5 week- and 6 month-old mdx/Ager–/– mice showed significantly reduced numbers of necrotic myofibers, and reduced areas of immune cell infiltrate compared with age-matched mdx mice. Also, muscles of mdx/Ager–/– mice showed strongly reduced expression of the marker of activated macrophages, MAC3, compared with mdx mice. Moreover, muscles of mdx/Ager–/– mice exhibited significantly reduced PAX7+ve and myogenin+ve cell numbers, pointing to a reduced recruitment of muscle precursor cells and a more efficient regeneration in dystrophic mice lacking RAGE. Our results suggest that RAGE has an important role in sustaining inflammatory and degenerative processes in dystrophic muscles, and that inhibition of RAGE expression/activity might represent a potential therapeutic approach in DMD patients. 1. Sorci G, et al. Mol Cell Biol 2004;24:4880-94. 2. Riuzzi F, et al. J Cell Sci 2012;125:1440-54. 3. Haslbeck KM, et al. Acta Neuropathol 2005;110:247-54
Mdx/Ager–/– mice show reduced muscle necrosis and inflammation compared with mdx mice
SALVADORI, LAURA;Sagheddu, Roberta;CHIAPPALUPI, SARA;DONATO, Rosario Francesco;SORCI, Guglielmo
2016
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration due to lack of dystrophin, a protein essential for the integrity of sarcolemma during contraction. In DMD compensative degeneration/regeneration cycles determine a condition of chronic inflammation contributing to progressive muscle wasting. RAGE (receptor for advanced glycation end-products) is a multiligand receptor belonging to the immunoglobulin superfamily involved in physiological and pathological processes including inflammation and myogenesis [1]. RAGE is not expressed in adult muscle tissue, whereas it is expressed in regenerating myofibers 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 mdx/Ager–/– mouse lacking dystrophin and RAGE (Ager). We analyzed diaphragms and hind-limb muscles (i.e., tibialis anterior and quadriceps femoris) of mdx, mdx/Ager–/–, Ager–/– and WT mice at different ages (i.e., 2, 3, 4 and 5 weeks, and 3 and 6 months of age). We found that although the absence of RAGE in dystrophic mice did not affect the onset of the pathology, muscles of 5 week- and 6 month-old mdx/Ager–/– mice showed significantly reduced numbers of necrotic myofibers, and reduced areas of immune cell infiltrate compared with age-matched mdx mice. Also, muscles of mdx/Ager–/– mice showed strongly reduced expression of the marker of activated macrophages, MAC3, compared with mdx mice. Moreover, muscles of mdx/Ager–/– mice exhibited significantly reduced PAX7+ve and myogenin+ve cell numbers, pointing to a reduced recruitment of muscle precursor cells and a more efficient regeneration in dystrophic mice lacking RAGE. Our results suggest that RAGE has an important role in sustaining inflammatory and degenerative processes in dystrophic muscles, and that inhibition of RAGE expression/activity might represent a potential therapeutic approach in DMD patients. 1. Sorci G, et al. Mol Cell Biol 2004;24:4880-94. 2. Riuzzi F, et al. J Cell Sci 2012;125:1440-54. 3. Haslbeck KM, et al. Acta Neuropathol 2005;110:247-54I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
