MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

Alexander, Matthew S.; Kawahara, Genri; Matsuki, Norio; Casar, Juan Carlos; Eisenberg, Iris; Myers, John M.; Gasperini, Molly; Estrella, Elicia; Kho, Alvin T.; Mitsuhashi, Satomi; Shapiro, Frederic; Kang, Peter B.; Kunkel, Louis M.

doi:10.1038/cdd.2013.62

Cited by 126 publications

(118 citation statements)

References 59 publications

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“…The results of previous studies have also indicated that miR-199a-5p could target several factors that regulate cell proliferation within the WNT signaling pathway, including FZD4 and WNT2 (Alexander et al 2013). Our data provide new evidence that miR-199a-5p plays a dominant role in GC-inhibited osteoblast proliferation.…”

Section: Discussionsupporting

confidence: 72%

“…Shi et al (2014a,b) showed that miR-199a-5p affects porcine preadipocyte proliferation and differentiation. Alexander et al (2013) found that miR-199a-5p affects WNT signaling, cell proliferation, and myogenic differentiation. Furthermore, lentivirus-mediated overexpression of miR199a-5p has been shown to inhibit cell proliferation in human hepatocellular carcinoma (Xu et al 2012a,b).…”

Section: Discussionmentioning

confidence: 99%

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Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling

Shi¹,

Huang²,

Kang³

et al. 2015

Journal of Molecular Endocrinology

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The inhibition of osteoblast proliferation by glucocorticoids (GCs) is very important in the etiology of GC-induced osteoporosis. The mechanisms of this process are still not fully understood. The results of recent studies have indicated an important role for microRNAs in GC-mediated responses in various cellular processes, including cell proliferation and apoptosis. Therefore, we developed the hypothesis that these regulatory molecules might be involved in GC-decreased osteoblast proliferation. Western blotting, quantitative realtime PCR, cell proliferation assays, and luciferase assays were employed to investigate the role of miRNAs in GC-inhibited osteoblast proliferation. microRNA-199a-5p was significantly increased in osteoblasts treated with dexamethasone (Dex). To delineate the role of microRNA-199a-5p, we silenced and overexpressed microRNA-199a-5p in osteoblasts. We found that overexpressing microRNA-199a-5p remarkably increased the inhibition effect of Dex on osteoblast proliferation, and depleting microRNA-199a-5p significantly attenuated Dex-inhibited osteoblast proliferation. Results of mechanistic studies indicated that microRNA-199a-5p inhibited FZD4 and WNT2 expression through a microRNA-199a-5p binding site within the 3 0 -UTR of FZD4 and WNT2. The post-transcriptional repression of FZD4 and WNT2 were further confirmed by luciferase reporter assay. These results indicated that microRNA-199a-5p may play a significant role in GC-inhibited osteoblast proliferation by regulating the WNT signaling pathway.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling

Shi¹,

Huang²,

Kang³

et al. 2015

Journal of Molecular Endocrinology

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“…others have profiled dysregulated microRNAs from 3 dystrophindeficient species (human, mouse, and zebrafish), and identified common microRNAs with a unique biosignature for the diseased state (35,85,86). Profiling of several of these microRNAs, including the muscle-enriched miR-1, miR-133a, and miR-206, have been shown as useful serum biomarkers in dystrophic mice (87).…”

Section: Dock3 Is An Essential Regulator Of Pten/akt and Rac1 Signalimentioning

confidence: 99%

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

Alexander¹,

Casar²,

Matsuki³

et al. 2014

J. Clin. Invest.

126

122

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Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which resultsin dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmd mdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmd mdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle-specific miR-486 overexpression in Dmd mdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle.

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“…For example, in patients with muscular defects, such as myopathies and atrophy, WNT/␤-catenin signaling is most likely altered due to a genetic and/or epigenetic cause(s) (80). Our results highlight that WNT/␤-catenin signaling is a widely used mechanism in skeletal muscles which regulate stepspecific targets during myogenesis.…”

Section: Discussionmentioning

confidence: 78%

WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets

Suzuki

Pelikan

Iwata

2015

Molecular and Cellular Biology

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cMolecules involved in WNT/␤-catenin signaling show specific spatiotemporal expression and play vital roles in myogenesis; however, it is still largely unknown how WNT/␤-catenin signaling regulates each step of myogenesis. Here, we show that WNT/ ␤-catenin signaling can control diverse biological processes of myogenesis by regulating step-specific molecules. In order to identify the temporally specific roles of WNT/␤-catenin signaling molecules in muscle development and homeostasis, we used in vitro culture systems for both primary mouse myoblasts and C2C12 cells, which can differentiate into myofibers. We found that a blockade of WNT/␤-catenin signaling in the proliferating cells decreases proliferation activity, but does not induce cell death, through the regulation of genes cyclin A2 (Ccna2) and cell division cycle 25C (Cdc25c). During muscle differentiation, the inhibition of WNT/␤-catenin signaling blocks myoblast fusion through the inhibition of the Fermitin family homolog 2 (Fermt2) gene. Blocking WNT/␤-catenin signaling in the well-differentiated myofibers results in the failure of maintenance of their structure by disruption of cadherin/␤-catenin/actin complex formation, which plays a crucial role in connecting a myofiber's cytoskeleton to the surrounding extracellular matrix. Thus, our results indicate that WNT/␤-catenin signaling can regulate multiple steps of myogenesis, including cell proliferation, myoblast fusion, and homeostasis, by targeting step-specific molecules.S keletal muscle plays highly specialized roles in the generation of force and is capable of extensive metabolic and functional plasticity. Skeletal muscle also exhibits robust regenerative capacity, and its formation is composed of complex and highly regulated processes among embryonic development and regeneration in mature skeletal musculature (1). Muscle precursor cells (also known as satellite cells in the adult) lie under, or are embedded in, the basal lamina of the myofiber in skeletal muscles and are the major source of regeneration and growth of skeletal muscles (2). During development and regeneration in response to injury or recovery from atrophy, muscle precursor cells start to proliferate, at which stage they are referred to as myoblasts, and subsequently differentiate to form new myofibers or fuse with existing myofibers (2). These processes require fine-tuned regulations of proliferation and differentiation that are likely regulated by signal transduction pathways.The WNT family (wingless-type mouse mammary tumor virus [MMTV] integration site family) of signaling molecules consists of 21 secreted glycoprotein ligands. WNT ligands are essential to activate downstream pathways (canonical ␤-catenin-dependent and/or noncanonical ␤-catenin-independent pathways) in physiological and pathological conditions. WNT/␤-catenin signaling can regulate a variety of genes in a specific spatiotemporal manner (3). In the absence of WNT ligands, ␤-catenin is incorporated into a protein complex containing axin, adenomatous polyposis coli (A...

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MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

Cited by 126 publications

References 59 publications

Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling

Glucocorticoid inhibits cell proliferation in differentiating osteoblasts by microRNA-199a targeting of WNT signaling

MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

WNT/β-Catenin Signaling Regulates Multiple Steps of Myogenesis by Regulating Step-Specific Targets

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