DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Berul, Charles I.; Maguire, Colin T.; Aronovitz, Mark; Greenwood, Jessica; Miller, Carol; Gehrmann, Josef; Housman, David E.; Mendelsohn, Michael E.; Reddy, Sita

doi:10.1172/jci5346

Cited by 182 publications

(119 citation statements)

References 35 publications

(38 reference statements)

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“…It has been shown that CTG repeats reduce expression of myotonin protein kinase in cis (4), causing abnormalities in cardiac muscle (5). CTG repeats also affect transcription of genes adjacent to myotonin protein kinase (6), leading to the development of cataracts (7,8).…”

Section: Dm1mentioning

confidence: 99%

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Timchenko

Patel

Iakova

et al. 2004

Journal of Biological Chemistry

187

205

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Accumulation of RNA CUG repeats in myotonic dystrophy type 1 (DM1) patients leads to the induction of a CUG-binding protein, CUGBP1, which increases translation of several proteins that are required for myogenesis. In this paper, we examine the role of overexpression of CUGBP1 in DM1 muscle pathology using transgenic mice that overexpress CUGBP1 in skeletal muscle. Our data demonstrate that the elevation of CUGBP1 in skeletal muscle causes overexpression of MEF2A and p21 to levels that are significantly higher than those in skeletal muscle of wild type animals. A similar induction of these proteins is observed in skeletal muscle of DM1 patients with increased levels of CUGBP1. Immunohistological analysis showed that the skeletal muscle from mice overexpressing CUGBP1 is characterized by a developmental delay, muscular dystrophy, and myofiber-type switch: increase of slow/oxidative fibers and the reduction of fast fibers. Examination of molecular mechanisms by which CUGBP1 up-regulates MEF2A shows that CUGBP1 increases translation of MEF2A via direct interaction with GCN repeats located within MEF2A mRNA. Our data suggest that CUGBP1-mediated overexpression of MEF2A and p21 inhibits myogenesis and contributes to the development of muscle deficiency in DM1 patients. DM11 is a multisystem disease mainly characterized by defects in skeletal muscle with the involvement of many tissues and systems such as cardiac muscle, brain, eye, and endocrine system (1). DM1 is caused by an expansion of CTG trinucleotide repeats within the 3Ј-untranslated region of the myotonin protein kinase gene (2). In DM1 patients, the size of DNA CTG expansion correlates with the severity of the disease. Patients with CTG expansion containing 50 -80 CTG repeats are almost asymptomatic. Individuals bearing the myotonin protein kinase gene with 100 -500 CTG repeats develop a disease in adult life (classical adult form of DM1) that is characterized by a progressive muscle wasting with myotonia. The most severe form of DM1, congenital disease, affects patients before or after birth and is associated with long CTG expansions (up to 2,000 repeats). This form of disease is characterized by a delay or arrest of skeletal muscle development (3). Although there is an overlap in range of repeats between different forms of DM1, there is a clear correlation of repeat number with severity of phenotype and reduction of age of onset.Investigations of molecular alterations in DM1 suggest that the expansion of CTG repeats causes the DM1 pathology through different mechanisms, mediated at both DNA and RNA levels. It has been shown that CTG repeats reduce expression of myotonin protein kinase in cis (4), causing abnormalities in cardiac muscle (5). CTG repeats also affect transcription of genes adjacent to myotonin protein kinase (6), leading to the development of cataracts (7,8). A number of recent studies indicate that other symptoms in DM1 such as myotonia (9, 10), delay of skeletal muscle differentiation (11,12), and a resistance to insulin (13) are mediated ...

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Section: Dm1mentioning

confidence: 99%

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Timchenko

Patel

Iakova

et al. 2004

Journal of Biological Chemistry

187

205

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“…30,33 Mice were studied 1 day after Holter recording. Briefly, animals underwent endotracheal intubation and were ventilated.…”

Section: Invasive Electrophysiological Study Protocolmentioning

confidence: 99%

Female Mice Lacking Estrogen Receptor β Display Prolonged Ventricular Repolarization and Reduced Ventricular Automaticity After Myocardial Infarction

et al. 2005

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Background-Major gender-based differences in the incidence of ventricular tachyarrhythmia after myocardial infarction have been shown in humans. Although the underlying mechanisms are unclear, earlier studies suggest that estrogen receptor-mediated effects play a major role in this process. Methods and Results-We examined the effect of estrogen receptor ␣ (ER␣) and estrogen receptor ␤ (ER␤) on the electrophysiological phenotype in female mice with and without chronic anterior myocardial infarction. There was no significant difference in overall mortality, infarct size, and parameters of left ventricular remodeling when we compared infarcted ER␣-deficient and ER␤-deficient mice with infarcted wild-type animals. In the 12-hour telemetric ECG recording 6 weeks after myocardial infarction, surface ECG parameters did not show significant differences in comparisons of ER␣-deficient mice versus wild-type controls, infarcted versus noninfarcted ER␣-deficient mice, and infarcted ER␣-deficient versus infarcted wild-type mice. However, infarcted ER␤-deficient versus noninfarcted ER␤-deficient mice showed a significant prolongation of the QT (

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“…Myoblast cell culture models 5,6 and subsequently a transgenic mouse model 7 have provided strong evidence for the involvement of RNA containing expanded CUG repeat tracts in aspects of DM1 skeletal muscle pathology. However, there is no clear model of RNA toxicity in the heart, and instead it has been suggested that DM1 cardiac pathology may be due to misexpression of DMPK 8,9 .…”

mentioning

confidence: 99%

Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy

et al. 2006

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Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG) n tract in the 3′ UTR of the gene encoding myotonic dystrophy protein kinase (DMPK) 1 , which results in nuclear entrapment of the 'toxic' mutant RNA and interacting RNAbinding proteins (such as MBNL1) in ribonuclear inclusions 2 . It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3′ UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3′ UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.Common features of adult-onset DM1 include myotonia, progressive skeletal muscle loss, cardiac conduction defects, smooth muscle dysfunction, cataracts and insulin resistance 2 . The normal number of CTG repeats (n = 5 to ~30) is higher (n = 50 to >3,000) in individuals with DM1 (ref. 1 ). Unlike the wild-type transcript, mutant DMPK mRNA forms nuclear aggregates 3,4 and is thought to trigger dominant effects by aberrant interactions with or altered activity of RNA splicing factors, principally members of the muscleblind-like (MBNL) family (such as MBNL1) and the CUG-BP and ETR3-like factor (CELF) family (such as CUG-BP1), leading to abnormal splicing of specific RNAs such as chloride channel (Clcn1), insulin Correspondence should be addressed to M.S.M. (mahadevan@virginia.edu). 4 These authors contributed equally to this work. AUTHOR CONTRIBUTIONSM.S.M., R.S.Y., Q.Y., C.D.F.-M., T.D.B. and L.H.P. performed experimental work and data analysis. S.B. generated the transgene constructs. M.S.M. was responsible for conceptual design and execution. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. One potential therapeutic approach in DM1 is to get rid of the toxic RNA from cells. However, it is unclear if this will alleviate the effects of the disease. We used the tetracycline (Tet) inducible system with the reverse tetracycline transactivator (rtTA) to generate double transgenic mice harboring (i) a Tet-responsive, DMPK promoter 10,11 -driven transgene (named GFP-DMPK 3′ UTR) expressing the DMPK 3′ UTR mRNA as part of a GFP transcript, and (ii) a constitutively expressed rtTA transgene (Fig. 1a) Fig. 1). Notably, RNA blots of skeletal muscle RNA showed two major species due to alternative use of polyadenylation signal...

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DMPK dosage alterations result in atrioventricular conduction abnormalities in a mouse myotonic dystrophy model

Cited by 182 publications

References 35 publications

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Overexpression of CUG Triplet Repeat-binding Protein, CUGBP1, in Mice Inhibits Myogenesis

Female Mice Lacking Estrogen Receptor β Display Prolonged Ventricular Repolarization and Reduced Ventricular Automaticity After Myocardial Infarction

Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy

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