miR-379 links glucocorticoid treatment with mitochondrial response in Duchenne muscular dystrophy

Mathilde Sanson (1) , Ai Vu Hong (1) , Emmanuelle Massourides (2) , Nathalie Bourg (1) , Laurence Suel (1) , Fatima Amor (1) , Guillaume Corre (1) , Paule Bénit (3) , Inès Barthélémy (4) , Stéphane Blot (4) , Anne Bigot (5) , Christian Pinset (2) , Pierre Rustin (3) , Laurent Servais (6, 7) , Thomas Voit (8) , Isabelle Richard (1) , David Israeli (1)

1 INTEGRARE - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares
2 I-STEM - Institut des cellules souches pour le traitement et l'étude des maladies monogéniques
3 NeuroDiderot (UMR_S_1141 / U1141) - Maladies neurodéveloppementales et neurovasculaires
4 IMRB - Institut Mondor de Recherche Biomédicale
5 Centre de recherche en Myologie – U974 SU-INSERM
6 University of Oxford
7 Université de Liège
8 UCL - University College of London [London]

Duchenne Muscular Dystrophy (DMD) is a lethal muscle disorder, caused by mutations in the DMD gene and affects approximately 1:5000-6000 male births. In this report, we identified dysregulation of members of the Dlk1-Dio3 miRNA cluster in muscle biopsies of the GRMD dog model. Of these, we selected miR-379 for a detailed investigation because its expression is high in the muscle, and is known to be responsive to glucocorticoid, a class of anti-inflammatory drugs commonly used in DMD patients. Bioinformatics analysis predicts that miR-379 targets EIF4G2, a translational factor, which is involved in the control of mitochondrial metabolic maturation. We confirmed in myoblasts that EIF4G2 is a direct target of miR-379, and identified the DAPIT mitochondrial protein as a translational target of EIF4G2. Knocking down DAPIT in skeletal myotubes resulted in reduced ATP synthesis and myogenic differentiation. We also demonstrated that this pathway is GC-responsive since treating mice with dexamethasone resulted in reduced muscle expression of miR-379 and increased expression of EIF4G2 and DAPIT. Furthermore, miR-379 seric level, which is also elevated in the plasma of DMD patients in comparison with age-matched controls, is reduced by GC treatment. Thus, this newly identified pathway may link GC treatment to a mitochondrial response in DMD.

Domaines: Biologie moléculaire; Génétique animale

Mathilde Sanson, Ai Vu Hong, Emmanuelle Massourides, Nathalie Bourg, Laurence Suel, et al.. miR-379 links glucocorticoid treatment with mitochondrial response in Duchenne muscular dystrophy. Scientific Reports, 2020, 10 (1), pp.9139. ⟨10.1038/s41598-020-66016-7⟩. ⟨inserm-02881214⟩