miR-486 is Essential for Muscle Function and Suppresses a Dystrophic Transcriptome

Authors

Adrienne Samani
Rylie M Hightower
Andrea L Reid
Katherine G English
Michael A Lopez
J Scott Doyle
Michael J Conklin
David A Schneider
Marcas M Bamman
Jeffrey J Widrick
David K Crossman
Min Xie
David Jee
Eric C Lai
Matthew S Alexander

Publication Date

9-1-2022

Journal

Life Science Alliance

Abstract

miR-486 is a muscle-enriched microRNA, or “myomiR,” that has reduced expression correlated with Duchenne muscular dystrophy (DMD). To determine the function of miR-486 in normal and dystrophin-deficient muscles and elucidate miR-486 target transcripts in skeletal muscle, we characterized mir-486 knockout mice (mir-486 KO). mir-486 KO mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects were exacerbated in mir-486 KO:mdx5cv (DKO) mice. To identify direct in vivo miR-486 muscle target transcripts, we integrated RNA sequencing and chimeric miRNA eCLIP sequencing to identify key transcripts and pathways that contribute towards mir-486 KO and dystrophic disease pathologies. These targets included known and novel muscle metabolic and dystrophic structural remodeling factors of muscle and skeletal muscle contractile transcript targets. Together, our studies identify miR-486 as essential for normal muscle function, a driver of pathological remodeling in dystrophin-deficient muscle, a useful biomarker for dystrophic disease progression, and highlight the use of multiple omic platforms to identify in vivo microRNA target transcripts.

Keywords

Animals, Dystrophin, Mice, Mice, Inbred mdx, MicroRNAs, Muscle, Skeletal, Transcriptome