Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy [Gene Regulation]

August 13th, 2015 by Mohamed, J. S., Hajira, A., Lopez, M. L., Boriek, A. M.

Muscular dystrophies (MDs) are a heterogeneous group of genetic and neuromuscular disorders, which result in severe loss of motor ability and skeletal muscle mass and function. Aberrant mechanotransduction and dysregulated-microRNA pathways are often associated with the progression of MD. Here, we hypothesized that dysregulation of mechanosensitive microRNAs (mechanomiRs) in dystrophic skeletal muscle play major roles in the progression of MD. To test our hypothesis, for the first time, we performed a genome-wide expression profile of anisotropically-regulated mechanomiRs and bioinformatically analyzed their target gene networks, and we assessed their roles in the advancement of MD using diaphragm muscles from wild-type and mdm (muscular dystrophy with myositis) mouse, an animal model of human tibial MD (titinopathy). We show that ex-vivo anisotropic mechanical stretch significantly alters the miRNA expression profile in diaphragm from WT and mdm mice, and as a result, some of the genes associated with MDs are dysregulated in mdm mice due to differential regulation of a distinct set of mechanomiRs. Interestingly, we found a contrasting expression pattern of the highly expressed let-7 family mechanomiRs let-7e-5p and miR-98-5p, and their target genes associated with extracellular matrix (ECM) and transforming growth factor-β signaling (TGF-β) pathways, respectively between WT and mdm mice. Gain- and loss-of-function analysis of let-7e-5p in myocytes isolated from the diaphragms of WT and mdm mice confirmed Col1a1, Col1a2, Col3a1, Col24a1, Col27a1, Itga1, Itga4, Scd1 and Thbs1 as target genes of let-7e-5p. Furthermore, we found that miR-98 negatively regulates myoblast differentiation. Our study therefore introducesanother biological player in the regulation of skeletal muscle structure and function that may contribute to unexplained disorders of MD.
  • Posted in Journal of Biological Chemistry, Publications
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