MicroRNAs Involved in Molecular Circuitries Relevant for the Duchenne Muscular Dystrophy Pathogenesis Are Controlled by the Dystrophin/nNOS Pathway

Cacchiarelli, Davide; Martone, Julie; Girardi, Erika; Cesana, Marcella; Incitti, Tania; Morlando, Mariangela; Nicoletti, Carmine; Santini, Tiziana; Sthandier, Olga; Barberi, Laura; Auricchio, Alberto; Musarò, Antonio; Bozzoni, Irene

doi:10.1016/j.cmet.2010.07.008

Cited by 224 publications

(276 citation statements)

References 43 publications

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“…miR-489, which is highly expressed in quiescent SCs and is quickly downregulated during SC activation, helps to maintain the quiescent state of adult stem-cell populations by targeting Dek 27 . When miRNA expression in skeletal muscle is dysregulated, various skeletal muscle disorders ensue, including skeletal muscle hypertrophy and muscular dystrophy [32][33][34] .…”

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confidence: 99%

MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice

Zhai

et al. 2015

Nat Commun

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Skeletal muscle stem cells, called satellite cells, are a quiescent heterogeneous population. Their heterogeneity is influenced by Pax7, a well-defined transcriptional regulator of satellite cell functions that defines two subpopulations: Pax7 Hi and Pax7 Lo . However, the mechanisms by which these subpopulations are established and maintained during myogenesis are not completely understood. Here we show that miR-431, which is predominantly expressed in the skeletal muscle, mediates satellite cell heterogeneity by fine-tuning Pax7 levels during muscle development and regeneration. In miR-431 transgenic mice, the Pax7 Lo subpopulation is enriched, enhances myogenic differentiation and accelerates muscle regeneration. Notably, miR-431 attenuates the muscular dystrophic phenotype in mdx mice and may be a potential therapeutic target in muscular diseases. miR-431 transgenic mice are a unique genetic model for investigating the cellular features and biological functions of Pax7 Lo satellite cells during muscle development and regeneration.

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confidence: 99%

MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice

Zhai

et al. 2015

Nat Commun

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“…9 MicroRNAs (miRNAs) have been shown to have an essential role in muscle development, differentiation, and disease. [10][11][12][13][14][15] Previously, we defined a miRNA biosignature of different muscle diseases and revealed dysregulated miRNAs that were either common or unique to each muscle disease. 12 Additional studies using the dystrophic mdx mouse muscle identified dysregulated miRNAs as a result of nNOS destabilization from the muscle membrane.…”

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confidence: 99%

“…12 Additional studies using the dystrophic mdx mouse muscle identified dysregulated miRNAs as a result of nNOS destabilization from the muscle membrane. 11 Nevertheless, studies in the mdx dystrophic mouse model have limitations in their clinical usefulness due to the lack of severity of the disease progression in the mouse muscles. The sapje dystrophinmutant zebrafish model is an excellent tool for studying dystrophic-muscle and disease progression, as the sapje mutants show dystrophic disease severity and can be analyzed in large numbers in a short period of time.…”

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confidence: 99%

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

et al. 2013

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In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophindeficient zebrafish, mdx 5cv mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation.

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“…[12][13][14] Deregulated expression of some myomiRs results in pathological conditions. [15][16][17] miRNA encoding genes are transcribed as primary miRNA transcripts (pri-miRNAs) by RNA polymerase II. The mechanism by which pri-miRNAs are processed first to stem-loop structured miRNA precursors (pre-miRNAs) and then to mature miRNAs involves two sequential endonucleolytic cleavages operated by multiprotein complexes including the RNase III enzymes Drosha, in the nucleus, and Dicer, in the cytoplasm (reviewed in Krol et al 18 ).…”

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confidence: 99%

PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

Briata¹,

Lin

Giovarelli

et al. 2011

Cell Death Differ

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Skeletal myogenesis is orchestrated by distinct regulatory signaling pathways, including PI3K/AKT, that ultimately control muscle gene expression. Recently discovered myogenic micro-RNAs (miRNAs) are deeply implicated in muscle biology. Processing of miRNAs from their primary transcripts is emerging as a major step in the control of miRNA levels and might be well suited to be regulated by extracellular signals. Here we report that the RNA binding protein KSRP is required for the correct processing of primary myogenic miRNAs upon PI3K/AKT activation in myoblasts C2C12 and in the course of injury-induced muscle regeneration, as revealed by Ksrp knock-out mice analysis. PI3K/AKT activation regulates in opposite ways two distinct KSRP functions inhibiting its ability to promote decay of myogenin mRNA and activating its ability to favor maturation of myogenic miRNAs. This dynamic regulatory switch eventually contributes to the activation of the myogenic program.

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MicroRNAs Involved in Molecular Circuitries Relevant for the Duchenne Muscular Dystrophy Pathogenesis Are Controlled by the Dystrophin/nNOS Pathway

Cited by 224 publications

References 43 publications

MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice

MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice

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

PI3K/AKT signaling determines a dynamic switch between distinct KSRP functions favoring skeletal myogenesis

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