Inhibition of miR-25 ameliorates cardiac and skeletal muscle dysfunction in aged mdx/utrn haploinsufficient (+/-) mice
- Title
- Inhibition of miR-25 ameliorates cardiac and skeletal muscle dysfunction in aged mdx/utrn haploinsufficient (+/-) mice
- Author
- 정동탁
- Keywords
- miR-25; ameliorates cardiac; skeletal muscle dysfunction
- Issue Date
- 2024-03-14
- Publisher
- CELL PRESS
- Citation
- MOLECULAR THERAPY NUCLEIC ACIDS
- Abstract
- Dystrophic cardiomyopathy is a significant feature of Duchenne muscular dystrophy (DMD). Increased cardiomyocyte cytosolic
calcium (Ca2+) and interstitial fibrosis are major pathophysiological hallmarks that ultimately result in cardiac dysfunction.
MicroRNA-25 (miR-25) has been identified as a suppressor of both sarcoplasmic reticulum calcium ATPase 2a (SERCA2a)
and mothers against decapentaplegic homolog-7 (Smad7) proteins. In this study, we created a gene transfer using an miR25 tough decoy (TuD) RNA inhibitor delivered via recombinant adeno-associated virus serotype 9 (AAV9) to evaluate the effect
of miR-25 inhibition on cardiac and skeletal muscle function in aged dystrophin/utrophin haploinsufficient mice mdx/utrn
(+/ ), a validated transgenic murine model of DMD. We found that the intravenous delivery of AAV9 miR-25 TuD resulted in
strong and stable inhibition of cardiac miR-25 levels, together with the restoration of SERCA2a and Smad7 expression. This
was associated with the amelioration of cardiomyocyte interstitial fibrosis as well as recovered cardiac function. Furthermore,
the direct quadricep intramuscular injection of AAV9 miR-25 TuD significantly restored skeletal muscle Smad7 expression,
reduced tissue fibrosis, and enhanced skeletal muscle performance in mdx/utrn (+/ ) mice. These results imply that miR25 TuD gene transfer may be a novel therapeutic approach to restore cardiomyocyte Ca2+ homeostasis and abrogate tissue
fibrosis in DMD.
- URI
- https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(24)00061-1https://repository.hanyang.ac.kr/handle/20.500.11754/189514
- ISSN
- 2162-2531
- DOI
- 10.1016/j.omtn.2024.102174
- Appears in Collections:
- COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY[E](과학기술융합대학) > ETC
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- PIIS2162253124000611.pdfDownload
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