Journal Article

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

Bourg, Nathalie, Voit, Thomas, Richard, Isabelle, Suel, Laurence, Corre, Guillaume, Barthelemy, Inès, Bénit, Paule, Blot, Stephane, Rustin, Pierre, Massourides, Emmanuelle, Amor, Fatima, Sanson, Mathilde, Vu Hong, Ai, Bigot, Anne, Pinset, Christian, Israeli, David, Servais, Laurent

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208 / 631/80/304 / 692/4017 / Adenosine Triphosphate - metabolism / Animal genetics / Animals / Anti-inflammatory agents / Binding Sites / Biochemistry, Molecular Biology / Bioinformatics / Biopsy / Dexamethasone / Dexamethasone - pharmacology / Disease Models, Animal / Dogs / Duchenne's muscular dystrophy / Dystrophin / Dystrophy / Eukaryotic Initiation Factor-4G - chemistry / Eukaryotic Initiation Factor-4G - genetics / Eukaryotic Initiation Factor-4G - metabolism / Gene Expression Regulation - drug effects / Genetics / Glucocorticoids / Glucocorticoids - therapeutic use / Human health sciences / Humanities and Social Sciences / Humans / Inflammation / Life Sciences / Mice / MicroRNAs - chemistry / MicroRNAs - metabolism / miRNA / Mitochondria / Mitochondria - metabolism / Mitochondrial Proton-Translocating ATPases - antagonists & inhibitors / Mitochondrial Proton-Translocating ATPases - genetics / Mitochondrial Proton-Translocating ATPases - metabolism / Mitochondrial Proton-Translocating ATPases/antagonists & inhibitors/genetics/metabolism / Molecular biology / multidisciplinary / Muscle, Skeletal - metabolism / Muscular dystrophy / Muscular Dystrophy, Duchenne - drug therapy / Muscular Dystrophy, Duchenne - genetics / Muscular Dystrophy, Duchenne/drug therapy/genetics / Myoblasts / Myoblasts, Skeletal - metabolism / Myotubes / Neurologie / Neurology / Pediatrics / Preadipocyte factor 1 / Pédiatrie / RNA Interference / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Sciences de la santé humaine / Skeletal muscle / Translation