Dataset Information

Regulation of DMD pathology by an ankyrin-encoded miRNA.

ABSTRACT:

Background

Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting from the production of a nonfunctional dystrophin protein. MicroRNA (miRNA) are small 21- to 24-nucleotide RNA that can regulate both individual genes and entire cell signaling pathways. Previously, we identified several mRNA, both muscle-enriched and inflammation-induced, that are dysregulated in the skeletal muscles of DMD patients. One particularly muscle-enriched miRNA, miR-486, is significantly downregulated in dystrophin-deficient mouse and human skeletal muscles. miR-486 is embedded within the ANKYRIN1(ANK1) gene locus, which is transcribed as either a long (erythroid-enriched) or a short (heart muscle- and skeletal muscle-enriched) isoform, depending on the cell and tissue types.

Results

Inhibition of miR-486 in normal muscle myoblasts results in inhibited migration and failure to repair a wound in primary myoblast cell cultures. Conversely, overexpression of miR-486 in primary myoblast cell cultures results in increased proliferation with no changes in cellular apoptosis. Using bioinformatics and miRNA reporter assays, we have identified platelet-derived growth factor receptor ?, along with several other downstream targets of the phosphatase and tensin homolog deleted on chromosome 10/AKT (PTEN/AKT) pathway, as being modulated by miR-486. The generation of muscle-specific transgenic mice that overexpress miR-486 revealed that miR-486 alters the cell cycle kinetics of regenerated myofibers in vivo, as these mice had impaired muscle regeneration.

Conclusions

These studies demonstrate a link for miR-486 as a regulator of the PTEN/AKT pathway in dystrophin-deficient muscle and an important factor in the regulation of DMD muscle pathology.

SUBMITTER: Alexander MS

PROVIDER: S-EPMC3188430 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Regulation of DMD pathology by an ankyrin-encoded miRNA.

Alexander Matthew S MS Casar Juan Carlos JC Motohashi Norio N Myers Jennifer A JA Eisenberg Iris I Gonzalez Robert T RT Estrella Elicia A EA Kang Peter B PB Kawahara Genri G Kunkel Louis M LM

Skeletal muscle 20110808

<h4>Background</h4>Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting from the production of a nonfunctional dystrophin protein. MicroRNA (miRNA) are small 21- to 24-nucleotide RNA that can regulate both individual genes and entire cell signaling pathways. Previously, we identified several mRNA, both muscle-enriched and inflammation-induced, that are dysregulated in the skeletal muscles of DMD patients. One particularly muscle-enriched miRNA, miR-486, is significantly downregula ...[more]

PMID: 21824387

Similar Datasets

Project description:Background:Left ventricular assist devices (LVADs) have revolutionized and improved the care of the sickest heart failure (HF) patients, and it is imperative that they receive appropriate ventricular unloading. Assessing this critical parameter with current methodologies (labs, imaging) is usually suboptimal in this patient population. Hence it is imperative to elucidate the molecular underpinnings involved in ventricular unloading. We have previously identified the cytoskeletal protein ?II spectrin as an essential nodal protein involved in post-translational targeting and ?II spectrin protein levels are significantly altered in multiple forms of human and animal HF. We therefore hypothesized that the ?II spectrin pathway would play a critical role in LVAD remodeling. Methods:Human heart failure samples were obtained from patients undergoing heart transplantation. Wild type (WT) mice and our previously validated ?II spectrin conditional knock out (?II cKO) mice were used for animal experiments. Transaortic constriction (TAC) was performed on WT mice. Protein expression was assessed via immunoblots, and protein interactions were assessed with co-immunoprecipitation. Transcriptome analysis was performed using isolated whole hearts from control adult WT mice (n = 3) compared to ?II cKO spectrin mice (n = 3). Results:We report that hearts from mice selectively lacking ?II spectrin expression in cardiomyocytes displayed altered transcriptional regulation of cardiac ankyrin repeat protein (CARP). Notably, CARP protein expression is increased after TAC. Additionally, our findings illustrate that prior to LVAD support, CARP levels are elevated in HF patients compared to normal healthy controls. Further, for the first time in a LVAD population, we show that elevated CARP levels in HF patients return to normal following LVAD support. Conclusion:Our findings illustrate that CARP is a dynamic molecule that responds to reduced afterload and stress, and has the potential to serve as a prognostic biomarker to assess for an adequate response to LVAD therapy.

Dataset Information

Regulation of DMD pathology by an ankyrin-encoded miRNA.

Background

Results

Conclusions

Publications

Regulation of DMD pathology by an ankyrin-encoded miRNA.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure