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

Myotonic dystrophy type 1 (DM1), the most common form of muscular dystrophy in adults, causes dominantly-inherited muscle weakness, defects of cardiac conduction, variable LV dysfunction, and risk of sudden death. The genetic basis is an expanded CTG repeat in the 3’ untranslated region of DMPK. DM1 patients are functionally hemizygous for DMPK protein, due to nuclear retention of mRNA having expanded repeats. The cardiac aspects are attributed to DMPK loss, toxicity of RNA with expanded repeats, or both. Dmpk heterozygous (+/-) and homozygous knockout (-/-) mice were reported to show AV conduction abnormalities resembling DM1 (Berul et al, JCI, 1999). In an effort to reduce RNA toxicity, antisense oligonucleotides (ASOs) targeting DMPK mRNA have recently entered clinical trials. DM1 phenotypes in skeletal muscle were corrected by ASO knockdown of toxic RNA in mice (Wheeler et al, Nature, 2012). While ASOs may have similar potential to mitigate RNA toxicity in the heart, there is risk of aggravated DMPK deficiency. To reexamine the role of DMPK in the conduction system we studied mice with Dmpk gene deletion or ASO knockdown. We obtained ECGs and echocardiograms on Dmpk -/- and +/- mice, compared to WT littermates. The +/- mice were treated with Dmpk-targeting ASOs or saline. Subcutaneous injection of 50 mg/kg/wk ASO was started at age 2 months, then shifted to biweekly injections after 6 weeks. Dmpk expression in hearts of +/- mice was ~50% of WT, and was further reduced by ASOs (84 ± 3% decrease of mRNA, 93 ± 2% decrease of protein, relative to WT). Surface ECGs and echocardiography at 6 and 10 months showed no differences of heart rate, cardiac conduction, or ejection fraction in WT, saline-treated +/-, ASO-treated +/-, or -/- mice. Conscious, unrestrained ECGs obtained at 11-12 months by radiotelemetry showed no differences among WT, saline-treated +/-, ASO-treated +/-, or -/- mice. We conclude that ASOs can induce posttranscriptional silencing of Dmpk in murine hearts. Constitutive absence of DMPK did not impact cardiac conduction or contractility, and the same was true for ASO knockdown to levels <15% of WT. Our data support the idea that cardiac dysfunction in DM1 results mainly from RNA toxicity, which potentially could be prevented or alleviated by ASOs.

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807-4 CUG expansions in a myotonic dystrophy mouse model cause cardiac conduction abnormalities and pathologic electrophysiology findings

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(04)90511-6 ◽

2004 ◽

Vol 43 (5) ◽

pp. A122 ◽

Cited By ~ 1

Author(s):

Cordula M Wolf ◽

Megan C Sherwood ◽

Dorothy Branco ◽

Sita Reddy ◽

Charles I Berul

Keyword(s):

Mouse Model ◽

Myotonic Dystrophy ◽

Cardiac Conduction ◽

Conduction Abnormalities

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Author response: Straightjacket/α2δ3 deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1

10.7554/elife.51114.sa2 ◽

2019 ◽

Author(s):

Emilie Auxerre-Plantié ◽

Masayuki Nakamori ◽

Yoan Renaud ◽

Aline Huguet ◽

Caroline Choquet ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Cardiac Conduction ◽

Author Response ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type

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Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

International Journal of Molecular Sciences ◽

10.3390/ijms20164017 ◽

2019 ◽

Vol 20 (16) ◽

pp. 4017 ◽

Cited By ~ 5

Author(s):

Kaalak Reddy ◽

Jana R. Jenquin ◽

John D. Cleary ◽

J. Andrew Berglund

Keyword(s):

Small Molecules ◽

Myotonic Dystrophy ◽

Small Molecule ◽

Disease Onset ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Rna Toxicity ◽

Complex Mechanisms ◽

Potential Use

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2).

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Mexiletine in myotonic dystrophy type-1

Neurology ◽

10.1212/wnl.0000000000011002 ◽

2020 ◽

pp. 10.1212/WNL.0000000000011002

Author(s):

Chad Heatwole ◽

Elizabeth Luebbe ◽

Spencer Rosero ◽

Katy Eichinger ◽

William Martens ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Cardiac Conduction ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Walk Distance ◽

Hand Grip ◽

Minute Walk Distance ◽

Minute Walk

ObjectiveTo assess mexiletine's long-term safety and effect on 6 minute walk distance in a well-defined cohort of myotonic dystrophy type-1 (DM1) patients.MethodsWe performed a randomized, double-blind, placebo-controlled trial of mexiletine (150 mg 3 times daily) to evaluate its efficacy and safety in a homogenous cohort of adult ambulatory DM1 patients. The primary outcome was change in 6-minute walk distance at 6 months. Secondary outcomes included changes in hand grip myotonia, strength, swallowing, forced vital capacity, lean muscle mass, Myotonic Dystrophy Health Index scores, and 24-hour Holter and EKG results at 3 and 6 months.ResultsForty-two participants were randomized and 40 completed the 6-month follow-up (n = 20 in both groups). No significant effects of mexiletine were observed on 6-minute walk distance, but hand grip myotonia was improved with mexiletine treatment. There were no differences between the mexiletine and placebo groups with respect to the frequency or type of adverse events. Changes in PR, QRS, and QTc intervals were similar in mexiletine and placebo-treated participants.ConclusionsThere was no benefit of mexiletine on six-minute walk distance at 6 months. Although mexiletine had a sustained positive effect on objectively measured hand grip myotonia, this was not seen in measures reflecting participants' perceptions of their myotonia. No effects of mexiletine on cardiac conduction parameters were seen over the 6-month follow-up period.Classification of evidenceThis study provides Class I evidence that for ambulatory patients with DM1 mexiletine does not significantly change six-minute walk distance at 6 months.

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Age of Onset of RNA Toxicity Influences Phenotypic Severity: Evidence from an Inducible Mouse Model of Myotonic Dystrophy (DM1)

PLoS ONE ◽

10.1371/journal.pone.0072907 ◽

2013 ◽

Vol 8 (9) ◽

pp. e72907 ◽

Cited By ~ 12

Author(s):

Jordan T. Gladman ◽

Mahua Mandal ◽

Varadamurthy Srinivasan ◽

Mani S. Mahadevan

Keyword(s):

Mouse Model ◽

Myotonic Dystrophy ◽

Age Of Onset ◽

Rna Toxicity

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Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy

ACS Chemical Biology ◽

10.1021/acschembio.5b00430 ◽

2015 ◽

Vol 10 (12) ◽

pp. 2706-2715 ◽

Cited By ~ 40

Author(s):

Suzanne G. Rzuczek ◽

Mark R. Southern ◽

Matthew D. Disney

Keyword(s):

Myotonic Dystrophy ◽

Small Molecule ◽

Rna Toxicity ◽

Small Molecule Library

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Myotonic Dystrophy

10.1093/med/9780190685157.003.0034 ◽

2018 ◽

Author(s):

Andrea Johnson

Keyword(s):

Skeletal Muscle ◽

Cognitive Impairment ◽

Sleep Apnea ◽

Myotonic Dystrophy ◽

Pediatric Patients ◽

Autosomal Dominant ◽

Anesthetic Management ◽

Cardiac Conduction ◽

Autosomal Dominant Disorder ◽

Skeletal Muscle Weakness

Myotonic dystrophy (DM) is a multisystemic autosomal dominant disorder. Individuals may present with symptoms at any age, but pediatric patients typically will present before 10 years of age. The clinical features of DM differ depending on the type of dystrophy and include skeletal muscle weakness, myotonia, sleep apnea, decreased gastrointestinal motility, insulin hypersecretion, cardiac conduction abnormalities, and occasionally cognitive impairment. Anesthetic management of the patient with DM should begin in the preoperative arena and should take into account the postoperative considerations and concerns for the patient with DM. This chapter will help the clinician develop an appropriate anesthetic plan and implement a safe and effective perioperative experience.

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Cardiac Conduction Disorders as Markers of Cardiac Events in Myotonic Dystrophy Type 1

Journal of the American Heart Association ◽

10.1161/jaha.119.015709 ◽

2020 ◽

Vol 9 (17) ◽

Cited By ~ 1

Author(s):

Hideki Itoh ◽

Takashi Hisamatsu ◽

Takuhisa Tamura ◽

Kazuhiko Segawa ◽

Toshiaki Takahashi ◽

...

Keyword(s):

Sudden Death ◽

Myotonic Dystrophy ◽

Cardiac Conduction ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Cardiac Events ◽

Conduction Disorders ◽

Qrs Duration

Background Myotonic dystrophy type 1 involves cardiac conduction disorders. Cardiac conduction disease can cause fatal arrhythmias or sudden death in patients with myotonic dystrophy type 1. Methods and Results This study enrolled 506 patients with myotonic dystrophy type 1 (aged ≥15 years; >50 cytosine‐thymine‐guanine repeats) and was treated in 9 Japanese hospitals for neuromuscular diseases from January 2006 to August 2016. We investigated genetic and clinical backgrounds including health care, activities of daily living, dietary intake, cardiac involvement, and respiratory involvement during follow‐up. The cause of death or the occurrence of composite cardiac events (ie, ventricular arrhythmias, advanced atrioventricular blocks, and device implantations) were evaluated as significant outcomes. During a median follow‐up period of 87 months (Q1–Q3, 37–138 months), 71 patients expired. In the univariate analysis, pacemaker implantations (hazard ratio [HR], 4.35; 95% CI, 1.22–15.50) were associated with sudden death. In contrast, PQ interval ≥240 ms, QRS duration ≥120 ms, nutrition, or respiratory failure were not associated with the incidence of sudden death. The multivariable analysis revealed that a PQ interval ≥240 ms (HR, 2.79; 95% CI, 1.9–7.19, P <0.05) or QRS duration ≥120 ms (HR, 9.41; 95% CI, 2.62–33.77, P < 0.01) were independent factors associated with a higher occurrence of cardiac events than those observed with a PQ interval <240 ms or QRS duration <120 ms; these cardiac conduction parameters were not related to sudden death. Conclusions Cardiac conduction disorders are independent markers associated with cardiac events. Further investigation on the prediction of occurrence of sudden death is warranted.

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