4.6 Article

miR-486 is essential for muscle function and suppresses a dystrophic transcriptome

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LIFE SCIENCE ALLIANCE
卷 5, 期 9, 页码 -

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LIFE SCIENCE ALLIANCE LLC
DOI: 10.26508/lsa.202101215

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  1. National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) F99/K00 [F99NS118718]
  2. NIH NINDS K08 grant [NS120812]
  3. Kaul Pediatric Research Institute
  4. NIH Nutrition & Obesity Research Center [P30DK056336]
  5. Mouse Cardiovascular Core Vevo 3100 Mouse Ultrasound Facility
  6. Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, HHS of the National Institutes of Health [R01HD095897]
  7. NIH NIAMS [R21AR074006, U01AR071133]
  8. Muscular Dystrophy Association (MDA) [MDA418254]
  9. NICHD [P2HD086851]
  10. NIH NHLBI [R01HL153501, R03HL141620]
  11. NIH [R01GM083300, R01HL135564]
  12. MSK [P30CA008748]

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miR-486 plays a significant role in muscle function, with reduced expression associated with Duchenne muscular dystrophy. It is essential for normal muscle function and contributes to pathological remodeling in dystrophin-deficient muscle. Additionally, it serves as a useful biomarker for disease progression. The use of multiple omic platforms is effective in identifying in vivo miR-486 target transcripts.
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:mdx(5cv) (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.

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