Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by mutations in the DMD gene. It affects around 1 in 5,000-6,000 boy births. In this report, the authors identified a deregulation of members of the miRNA Dlk1-Dio3 cluster in muscle biopsies of the GRMD dog model. Among these, they selected miR-379 to be analyzed in more detail because its expression is high in muscle and is known to be responsive to glucocorticoids (GC), a class of anti-inflammatory drugs commonly used in patients DMD.
Bioinformatics analysis predicts that miR-379 targets EIF4G2, a translation factor involved in the control of mitochondrial metabolic maturation. Researchers confirmed that, in myoblasts, EIF4G2 is a direct target of miR-379 and they identified the mitochondrial protein DAPIT as a translation target of EIF4G2. Removal of DAPIT from skeletal myotubes resulted in reduced ATP synthesis and myogenic differentiation. The authors also demonstrated that this pathway is responsive to GCs, since treatment of mice with dexamethasone resulted in a decrease in muscle expression of miR-379 and an increased expression of EIF4G2 and DAPIT. In addition, the serum level of miR-379, which is also elevated in the plasma of DMD patients compared to controls of the same age, is reduced by GC therapy.
Thus, this newly identified pathway can link GC treatment to a mitochondrial response in DMD.
