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Inhibition of miR-25 ameliorates cardiac and skeletal muscle dysfunction in aged mdx/utrn haploinsufficient (+/-) mice.
Kepreotis, Sacha V; Oh, Jae Gyun; Park, Mina; Yoo, Jimeen; Lee, Cholong; Mercola, Mark; Hajjar, Roger J; Jeong, Dongtak.
Afiliación
  • Kepreotis SV; Cardiovascular Research Institute, Icahn School of Medicine, Mount Sinai, NY, USA.
  • Oh JG; Cardiovascular Research Institute, Icahn School of Medicine, Mount Sinai, NY, USA.
  • Park M; Department of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University-ERICA, Ansan, South Korea.
  • Yoo J; Cardiovascular Research Institute, Icahn School of Medicine, Mount Sinai, NY, USA.
  • Lee C; Department of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University-ERICA, Ansan, South Korea.
  • Mercola M; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Hajjar RJ; Mass General Brigham Gene and Cell Therapy Institute, Boston, MA, USA.
  • Jeong D; Department of Medicinal and Life Science, College of Science and Convergence Technology, Hanyang University-ERICA, Ansan, South Korea.
Mol Ther Nucleic Acids ; 35(2): 102174, 2024 Jun 11.
Article en En | MEDLINE | ID: mdl-38584818
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 miR-25 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 miR-25 TuD gene transfer may be a novel therapeutic approach to restore cardiomyocyte Ca2+ homeostasis and abrogate tissue fibrosis in DMD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Nucleic Acids Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Mol Ther Nucleic Acids Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos