DMD – Animal Models

Abstract

Duchenne muscular dystrophy (DMD) is a lethal muscle disease, caused by mutations in the DMD gene, encoding a protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequences of disruption of the link due to lack of functional dystrophin involved sarcolemma destabilization, perturbation of Ca 2 + homeostasis, activation of proteases, mitochondrial damage, leading to tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue. However, the mechanism and nature of the metabolic dysregulation are yet poorly understood. In the present study, we characterized a molecular mechanism of metabolic perturbation in DMD. We sequenced plasma miRNA in a DMD cohort, comprising of 54 DMD patients treated or not by glucocorticoid, compared to 27 healthy controls, in three age groups. We identified 96 dysregulated miRNAs, 74 up and 22 down in DMD. We confirmed the dysregulation in DMD of the Dystro-miRs, Cardio-miRs and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs, yet unreported in DMD. We developed an original dual bioinformatics approach, based on both miRNAs' target and host genes, for the biological interpretation of miRNA dysregulation. This analysis predicted that dysregulation of lipid metabolism has a central role in DMD. Investigation of skeletal muscles of the mdx mouse, a model of DMD, revealed dysregulation of SREBP1 and SREBP2, two key transcription factors of cholesterol and fatty acid metabolism, perturbation of the mevalonate pathway, and accumulation of cholesterol. Elevated cholesterol was also found in biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a hypolipidemic statin, normalized these perturbations and partially restored dystrophic parameters. This investigation supports that cholesterol metabolism and the mevalonate pathway are therapeutic targets in DMD.