Muscle fiber plays a critical role in therapeutic response to glucocorticoids during myositis

Résumé :

Introduction. Myositis are autoimmune diseases characterized by chronic inflammation of skeletal muscle and muscle weakness.
Glucocorticoids (GC), the first line treatment of myositis, improve muscle strength, but recovery is partial and, chronically, they lead to steroid myopathy. Thus, myositis care has to be improved. GC effects are mediated by glucocorticoid receptor (GR), which is expressed in various cell types including immune cells and myofibers, but it remains to be determined which cells are leading to therapeutic response.
Materials and methods. At day (D) 0 we induced myositis in transgenic mice with an inducible GR knockout selective for myofiber (GR(i)skm-/-) and in control mice. Prednisone (PDN) was administered after GR ablation at D14 (1 mg/kg/day for 7 days). Muscle strength was assessed at D0, 14 and 20. Mice were euthanized at D21.
We compared GR(i)skm-/- and control mice treated by PDN or vehicle by grip test, histology and flow cytometry.
Results. Muscle strength was decreased in GR(i)skm-/- and control mice from D14 to D20 in vehicle groups. Control mice but not GR(i)skm-/- recovered muscle strength after PDN.
At H&E and Gomori trichrome staining, no quantitative differences among the four conditions were found in inflammatory infiltrate and necrotic fibers.
Nevertheless, in control mice, PDN induced a 3-fold decrease in CD8+ cells compared to vehicle group (p<0,05). This effect of PDN was abolished in GR(i)skm-/- mice.
Conclusions. GR in myofiber is crucial for GC therapeutic response in myositis. Particularly, GC polarize inflammatory infiltrate toward an anti-inflammatory response, through a specific effect on myofiber.

Mots clés : myositis, glucocorticoids, glucocorticoid receptor, GR, muscle fiber, myofiber

Auteurs : Giannini Margherita, Rovito Daniela, Débrut Léa, Charles Anne-Laure, Duteil Delphine, Geny Bernard, Metzger Daniel, Laverny Gilles, Meyer Alain

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