Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1

Kimura, Takashi; Nakamori, Mikihito; Lueck, John D.; Pouliquin, Pierre; Aoike, Futoshi; Fujimura, Harutoshi; Dirksen, Robert T.; Takahashi, Masanori; Dulhunty, Angela F.; Sakoda, Saburo

doi:10.1093/hmg/ddi223

Cited by 250 publications

(280 citation statements)

References 45 publications

Supporting

Mentioning

260

Contrasting

Unclassified

Order By: Relevance

“…To assess the downstream effect of expanded CUG transcript degradation on aberrant splicing, we examined the alternative splicing of three DM1-associated splicing events: Cypher, Serca1, and Clcn1 (20)(21)(22). At time points more than 2 wk after tamoxifen injection, all three events reverted toward the embryonic splicing pattern as expected (Fig.…”

Section: Cag Gapmers Induce Degradation Of Expanded Dmpk Transcripts Inmentioning

confidence: 54%

RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1

Lee

Bennett

Cooper

2012

Proc. Natl. Acad. Sci. U.S.A.

143

134

View full text Add to dashboard Cite

Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease caused by abnormal transcripts containing expanded CUG repeats. The CUG transcripts aggregate in the nucleus to form RNA foci and lead to nuclear depletion of Muscleblind-like 1 (MBNL1) and stabilized expression of CUGBP Elav like family 1 (CELF1), both of which are splicing regulatory proteins. The imbalance of these proteins results in misregulation of alternative splicing and neuromuscular abnormalities. Here, we report the use of antisense oligonucleotides (ASOs) as a therapeutic approach to target the pathogenic RNA in DM1. We designed chimeric ASOs, termed gapmers, containing modified nucleic acid residues to induce RNase H-mediated degradation of CUG-repeat transcripts. The gapmers selectively knockdown expanded CUG transcripts and are sufficient to disrupt RNA foci both in cell culture and mouse models for DM1. Furthermore, combination of gapmers with morpholino ASOs that help release binding of MBNL1 to the toxic RNA can potentially enhance the knockdown effect. Additional optimization will be required for systemic delivery; however, our study provides an alternative strategy for the use of ASOs in DM1 therapy.microsatellite expansion | muscular dystrophy | phosphorothioate | gapmer

show abstract

Section: Cag Gapmers Induce Degradation Of Expanded Dmpk Transcripts Inmentioning

confidence: 54%

RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1

Lee

Bennett

Cooper

2012

Proc. Natl. Acad. Sci. U.S.A.

143

134

View full text Add to dashboard Cite

show abstract

“…The longer t EMG-MMG in DM1 may be explained by the alteration in the splicing of several proteins, such as SERCA1 and CACNA1S, involved in Ca 2+ homeostasis and in excitation-contraction coupling mechanism [6][7][8][9][10] thus possibly leading to a lengthened duration of the dihydropyridine and ryanodine receptors interaction, Ca 2+ release by sarcoplasmic reticulum, and troponin activation [9,10,35].…”

Section: Delays During Muscle Contractionmentioning

confidence: 99%

“…Experimental evidence demonstrates that an alteration in the splicing of several proteins involved in Ca 2+ homeostasis and in excitation-contraction coupling mechanisms may play a pivotal role [6][7][8][9][10]. Myotonia is characterised by a state of pathologically enhanced muscle excitability, in which involuntary trains of action potentials cause a delay in muscle relaxation after contraction [11].…”

Section: Introductionmentioning

confidence: 99%

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

Esposito

Cè

Rampichini

et al. 2016

Neuromuscular Disorders

View full text Add to dashboard Cite

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Highlights Patients with myotonic dystrophy type 1 (DM1) were investigated isometrically  We calculated the electromechanical delays during muscle contraction and relaxation  Delays were partitioned into electrochemical and mechanical components  Measurements reliability was very high in both patients and controls  Delays were longer in DM1, especially during muscle relaxation AbstractThe electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Components duration and measurements reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n=13) and in healthy controls (n=13). EMG, mechanomyogram, and force were recorded in DM1 and in age-and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles.Measurements reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions.

show abstract

“…26 However, thus far, no direct evidence demonstrated that the splicing misregulation of INSR and TNNT2 genes leads to, respectively, insulin resistance and conduction defects in DM1. Several other pre-mRNA transcripts regulated by MBNL1 and CUGBP1 proteins are aberrantly spliced in DM1, such as sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 1 (ATP2A1, also known as SERCA1), 48 ryanodine receptor (RyR), 48 fast skeletal troponin T (TNNT3), 49 and myotubularin-related protein 1 (MTMR1). 50 Data that support the involvement of MBNL1 and CUGBP1 splicing factors in DM1 pathogenesis come from mouse models that have recapitulated DM splicing patterns and related skeletal and cardiac muscle abnormalities through either gene knock-out of Mbnl1, 49 or transgenic overexpression of CUGBP1.…”

confidence: 99%

CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

Wojciechowska

Krzyżosiak

2011

RNA Biology

View full text Add to dashboard Cite

Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1

Cited by 250 publications

References 45 publications

RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1

RNase H-mediated degradation of toxic RNA in myotonic dystrophy type 1

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1

CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders

Contact Info

Product

Resources

About