Abstract
Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder resulting in muscle weakness and cardiomyopathy. MicroRNAs have been shown to play essential roles in muscle development, metabolism, and disease pathologies. We demonstrated that miR-486 expression is reduced in DMD muscles and its expression levels correlate with dystrophic disease severity. MicroRNA-486 knockout mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects that were exacerbated on the dystrophic mdx5cv background. We integrated RNA-sequencing and chimeric eCLIP-sequencing data to identify direct in vivo targets of miR-486 and associated dysregulated gene signatures in skeletal muscle. In comparison to our DMD mouse muscle transcriptomes, we identified several of these miR-486 muscle targets including known modulators of dystrophinopathy disease symptoms. Together, our studies identify miR-486 as a driver of muscle remodeling in DMD, a useful biomarker for dystrophic disease progression, and highlight chimeric eCLIP-sequencing as a useful tool to identify direct in vivo microRNA target transcripts.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* co-first authors
Emails of Authors: rylieh{at}uab.edu, asamani{at}uab.edu, areid01{at}uab.edu, ke111{at}uab.edu, mlopez{at}peds.uab.edu, jdoyle{at}uabmc.edu, mconklin{at}uabmc.edu, dschneid{at}uab.edu, mbamman{at}ihmc.us, jeffrey.widrick{at}childrens.harvard.edu, dkcrossm{at}uab.edu, mxie{at}uabmc.edu, david.h.jee{at}gmail.com, laie{at}mskcc.org, malexander{at}peds.uab.edu
List of Abbreviations
- Ago2
- Argonaute-2
- ANK1
- Ankyrin1
- BMD
- Becker muscular dystrophy
- CDS
- coding sequence
- ChIP
- chromatin immunoprecipitation
- eCLIP
- enhanced cross-linking and immunoprecipitation
- CSA
- cross-sectional area
- DAPC
- Dystrophin-associated complex
- DEXA
- dual energy x-ray absorptiometry
- DMD
- Duchenne muscular dystrophy
- ECM
- extracellular matrix
- GTT
- glucose tolerance test
- IGV
- Integrated Genome Viewer
- MyHC
- myosin heavy chain
- MSC
- muscle satellite cell
- PMO
- phosphorodiamidate morpholino oligomer
- QMR
- Quantitative Magnetic Resonance
- qPCR
- quantitative polymerase chain reaction
- sANK1
- small Ankryin1/Ank1-5
- Seq
- sequencing
- TA
- Tibialis anterior