Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy

Chen, Guiying; Matsubara, Akio; Konishi, Hiroyuki; Ohkawara, Bisei; Ito, Mikako; Kinoshita, M.; Kiyama, Hiroshi; Matsuura, Tetsuya; Ohno, Kinji

doi:10.1038/srep25317

Cited by 28 publications

(40 citation statements)

References 38 publications

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“…Small molecules have also been designed to target pathways more downstream, such as inducing overexpression of MBNL1, a method that has shown promising results [122]. Another molecule currently in the spotlight is tideglusib, a selective and irreversible non-ATP-competitive glycogen synthase kinase 3 inhibitor.…”

Section: Small Molecule Therapeuticsmentioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

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Section: Small Molecule Therapeuticsmentioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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“…A previous study showed that 2-fold upregulation of MBNL1 protein by transduction of a recombinant adeno-associated viral vector reversed missplicing of Clcn1, Ldb3, Serca1, and Tnnt3, resulting in a significant reduction in myotonia in a DM1 mouse model 17 . We also reported that ~1.5-folds upregulation of MBNL1 protein by phenylbutazone, a non-selective NSAID, reversed missplicing of Clcn1, Nfix, and Rpn2, and improved muscle weakness in a DM1 mouse model 21 . These results suggest that upregulation of MBNL1 effectively ameliorates aberrant splicing in DM1 muscle cells, in which the MBNL1-availability is severely impaired.…”

Section: Discussionmentioning

confidence: 71%

“…We previously identified a transcription enhancer, named MeR2, in Mbnl1 intron 1, and reported that the demethylation of the MeR2 enhancer upregulated Mbnl1 expression ( Fig. 4a) 21 . To examine whether NSAIDs upregulate the activity of the MeR2 enhancer, we inserted the MeR2 enhancer upstream of the SV40 promoter and the firefly luciferase cDNA to make pGL3P-MeR2 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Drug screening for 29 NSAIDs to elevate Mbnl1 mRNA expression. We previously reported that phenylbutazone, a non-selective NSAID, enhances MBNL1 expression in myogenic cells 21 . We here screened 29 NSAIDs to examine a class effect of NSAIDs on enhancement of Mbnl1 expression.…”

Section: Resultsmentioning

confidence: 99%

“…Our study shows that nearly a half of the screened NSAIDs enhanced Mbnl1 expression in myogenic cells, suggesting possible application of NSAIDs for DM1 patients. Indeed, phenylbutazone, a non-selective COX inhibitor, ameliorates muscle weakness and muscle pathology in DM1 mouse model 21 . The beneficial effects of NSAIDs on skeletal muscles are not limited to DM1.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells

Huang

Matsubara

Chen

et al. 2020

Sci Rep

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Muscleblind-like 1 (MBNL1) is a ubiquitously expressed RNA-binding protein, which is highly expressed in skeletal muscle. Abnormally expanded CUG-repeats in the DMPK gene cause myotonic dystrophy type 1 (DM1) by sequestration of MBNL1 to nuclear RNA foci and by upregulation of another RNAbinding protein, CUG-binding protein 1 (CUGBP1). We previously reported that a nonsteroidal antiinflammatory drug (NSAID), phenylbutazone, upregulates MBNL1 expression in DM1 mouse model by demethylation of MeR2, an enhancer element in Mbnl1 intron 1. NSAIDs inhibit cyclooxygenase (COX), which is comprised of COX-1 and COX-2 isoforms. In this study, we screened 29 NSAIDs in C2C12 myoblasts, and found that 13 NSAIDs enhanced Mbnl1 expression, where COX-1-selective NSAIDs upregulated Mbnl1 more than COX-2-selective NSAIDs. Consistently, knockdown of COX-1, but not of COX-2, upregulated MBNL1 expression in C2C12 myoblasts and myotubes, as well as in myotubes differentiated from DM1 patient-derived induced pluripotent stem cells (iPSCs). Luciferase assay showed that COX-1-knockdown augmented the MeR2 enhancer activity. Furthermore, bisulfite sequencing analysis demonstrated that COX-1-knockdown suppressed methylation of MeR2. These results suggest that COX-1 inhibition upregulates Mbnl1 transcription through demethylation of the MeR2 enhancer. Taken together, our study provides new insights into the transcriptional regulation of Mbnl1 by the COX-1-mediated pathway. Muscleblind-like (MBNL) is a multifunctional RNA binding protein that modulates diverse RNA metabolisms, including splicing, polyadenylation, stability, and localization of mRNA 1-3. There are three isoforms of MBNL in mammals (MBNL1, MBNL2, and MBNL3), in which MBNL1 is the most ubiquitously expressed isoform and is highly expressed in skeletal muscle 4. Expression of MBNL1 is elevated in skeletal muscle during myogenic differentiation 5. Knockout of Mbnl1 results in pathology reminiscent of myotonic dystrophy type 1 (DM1) with abnormal terminal muscle differentiation 6-8. DM1 is the most common form of muscular dystrophies in adults, and is caused by abnormal expansion of CTG repeats in the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene on chromosome 19 9,10. The transcribed CUG repeats from the CTG repeats make abnormal RNA foci in the nucleus, leading to sequestration of MBNL1 and upregulation of another RNA binding protein, CUG-binding protein 1 (CUGBP1) 11. Downregulation of MBNL1 availability leads to aberrant regulation of alternative splicing of hundreds of genes, which causes various manifestations such as myotonia, progressive muscle wasting, cataracts, insulin resistance, cardiac arrhythmia, and intellectual deficits 8,12,13. Several therapeutic strategies for DM1 are currently under investigation 14-16. Induction of MBNL1 expression is one of the promising therapies for DM1. Overexpression of Mbnl1 in skeletal muscle with an adeno-associated

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Partners in crime: Proteins implicated in RNA repeat expansion diseases

et al. 2022

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Short tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNA exp ) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNA exp molecules and multiple protein partners, in this review, we discuss the roles of selected RNA-binding proteins (RBPs) that interact with RNA exp and thus act as "partners in crime" in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNA exp life cycle, such as transcription, splicing, transport, and AUG-independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNA exp within nuclear foci and those which participate in RNA exp -dependent innate immunity activation.Abbreviations: 3 0 UTR/5 0 UTR, 3 0 /5 0 untranslated regions; AS, alternative splicing; ASO, antisense oligonucleotide; C9-ALS/FTD, C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia; CAG exp , expanded CAG repeats; CCUG exp , expanded CCUG repeats; CGG exp , expanded CGG repeats; CTG exp , expanded CTG repeats; CUG exp , expanded CUG repeats;

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Phenylbutazone induces expression of MBNL1 and suppresses formation of MBNL1-CUG RNA foci in a mouse model of myotonic dystrophy

Cited by 28 publications

References 38 publications

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Inhibition of cyclooxygenase-1 by nonsteroidal anti-inflammatory drugs demethylates MeR2 enhancer and promotes Mbnl1 transcription in myogenic cells

Partners in crime: Proteins implicated in RNA repeat expansion diseases

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