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

Abstract : 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.
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Submitted on : Thursday, June 25, 2020 - 2:52:49 PM
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Misú 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, Nature Publishing Group, 2020, 10 (1), pp.9139. ⟨10.1038/s41598-020-66016-7⟩. ⟨inserm-02881214⟩

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