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Journal of Translational Medicine Dec 2022Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3' untranslated...
BACKGROUND
Myotonic dystrophy type 1 (DM1), one of the most common forms of adult-onset muscular dystrophy, is caused by abnormally expanded CTG repeats in the 3' untranslated region of the DMPK gene. The CUG repeats transcribed from the expanded CTG repeats sequestrate a splicing factor, MBNL1, causing the clinical symptoms in DM1. Nowadays, only symptomatic treatments are available for DM1, and no rational therapy is available. Recently, upregulation of MBNL1 expression has been found to be one of the promising therapies for DM1.
METHODS
All experiments were conducted in the C2C12 myoblasts and HSA mice, a DM1 mouse model. Real-time PCR and western blot were used to detect the mRNA and protein level, respectively. The rotarod exercise, grip strength and hanging time were used to evaluate the muscle strength of mice.
RESULTS
In this study, we demonstrated that calcitriol, an active form of vitamin D3, increased MBNL1 in C2C12 mouse myoblasts as well as in HSA mice model for DM1. In HSA mice model, calcitriol improved muscle strength, and corrected aberrant splicing in skeletal muscle. Besides, calcitriol reduced the number of central nuclei, and improved muscle histopathology in HSA mice. In addition, we identified that calcitriol upregulated MBNL1 expression via activating the promoter of Mbnl1 in C2C12 myogenic cells.
CONCLUSION
Our study suggests that calcitriol is a potential pharmacological strategy for DM1 that enhances MBNL1 expression.
Topics: Mice; Animals; Myotonic Dystrophy; Calcitriol; RNA-Binding Proteins; Myoblasts; Disease Models, Animal; Muscle, Skeletal; Alternative Splicing; DNA-Binding Proteins
PubMed: 36510245
DOI: 10.1186/s12967-022-03806-9 -
International Journal of Environmental... Feb 2021Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary and multisystemic disease, characterized by progressive distal muscle weakness and myotonia. Despite... (Review)
Review
Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary and multisystemic disease, characterized by progressive distal muscle weakness and myotonia. Despite huge efforts, the pathophysiological mechanisms underlying DM1 remain elusive. In this review, the metabolic alterations observed in patients with DM1 and their connection with lipin proteins are discussed. We start by briefly describing the epidemiology, the physiopathological and systemic features of DM1. The molecular mechanisms proposed for DM1 are explored and summarized. An overview of metabolic syndrome, dyslipidemia, and the summary of metabolic alterations observed in patients with DM1 are presented. Patients with DM1 present clinical evidence of metabolic alterations, namely increased levels of triacylglycerol and low-density lipoprotein, increased insulin and glucose levels, increased abdominal obesity, and low levels of high-density lipoprotein. These metabolic alterations may be associated with lipins, which are phosphatidate phosphatase enzymes that regulates the triacylglycerol levels, phospholipids, lipid signaling pathways, and are transcriptional co-activators. Furthermore, lipins are also important for autophagy, inflammasome activation and lipoproteins synthesis. We demonstrate the association of lipin with the metabolic alterations in patients with DM1, which supports further clinical studies and a proper exploration of lipin proteins as therapeutic targets for metabolic syndrome, which is important for controlling many diseases including DM1.
Topics: Humans; Lipids; Muscle Weakness; Myotonic Dystrophy; Organic Chemicals
PubMed: 33673200
DOI: 10.3390/ijerph18041794 -
International Journal of Molecular... Nov 2021Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth... (Review)
Review
Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy affecting adults and children, is a multi-systemic disorder affecting skeletal, cardiac, and smooth muscles as well as neurologic, endocrine and other systems. This review is on the cardiac pathology associated with DM1. The heart is one of the primary organs affected in DM1. Cardiac conduction defects are seen in up to 75% of adult DM1 cases and sudden death due to cardiac arrhythmias is one of the most common causes of death in DM1. Unfortunately, the pathogenesis of cardiac manifestations in DM1 is ill defined. In this review, we provide an overview of the history of cardiac studies in DM1, clinical manifestations, and pathology of the heart in DM1. This is followed by a discussion of emerging data about the utility of cardiac magnetic resonance imaging (CMR) as a biomarker for cardiac disease in DM1, and ends with a discussion on models of cardiac RNA toxicity in DM1 and recent clinical guidelines for cardiologic management of individuals with DM1.
Topics: Animals; Humans; Muscles; Myotonic Dystrophy
PubMed: 34769305
DOI: 10.3390/ijms222111874 -
International Journal of Molecular... Dec 2021Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide... (Review)
Review
Myotonic dystrophy is the most common muscular dystrophy in adults. It consists of two forms: type 1 (DM1) and type 2 (DM2). DM1 is associated with a trinucleotide repeat expansion mutation, which is transcribed but not translated into protein. The mutant RNA remains in the nucleus, which leads to a series of downstream abnormalities. DM1 is widely considered to be an RNA-based disorder. Thus, we consider three areas of the RNA pathway that may offer targeting opportunities to disrupt the production, stability, and degradation of the mutant RNA.
Topics: Cell Nucleus; Gene Regulatory Networks; Humans; Myotonic Dystrophy; RNA Stability; RNA, Messenger; Trinucleotide Repeat Expansion
PubMed: 34948025
DOI: 10.3390/ijms222413225 -
Drug Discovery Today Nov 2017Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene.... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a rare multisystemic neuromuscular disorder caused by expansion of CTG trinucleotide repeats in the noncoding region of the DMPK gene. Mutant DMPK transcripts are toxic and alter gene expression at several levels. Chiefly, the secondary structure formed by CUGs has a strong propensity to capture and retain proteins, like those of the muscleblind-like (MBNL) family. Sequestered MBNL proteins cannot then fulfill their normal functions. Many therapeutic approaches have been explored to reverse these pathological consequences. Here, we review the myriad of small molecules that have been proposed for DM1, including examples obtained from computational rational design, HTS, drug repurposing, and therapeutic gene modulation.
Topics: Animals; Drug Design; Drug Repositioning; Gene Expression Regulation; High-Throughput Screening Assays; Humans; Myotonic Dystrophy; Myotonin-Protein Kinase; Trinucleotide Repeats
PubMed: 28780071
DOI: 10.1016/j.drudis.2017.07.011 -
JACC. Clinical Electrophysiology Aug 2021
Topics: Death, Sudden, Cardiac; Electrocardiography; Humans; Myotonic Dystrophy; Precision Medicine
PubMed: 34412868
DOI: 10.1016/j.jacep.2021.07.002 -
Neurotherapeutics : the Journal of the... Oct 2018Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem... (Review)
Review
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.
Topics: Animals; Disease Management; Humans; Mutation; Myotonic Dystrophy; Myotonin-Protein Kinase; RNA-Binding Proteins
PubMed: 30341596
DOI: 10.1007/s13311-018-00679-z -
F1000Research 2018This review discusses current bottlenecks in making CRISPR-Cas9-mediated genome editing a therapeutic reality and it outlines recent strategies that aim to overcome... (Review)
Review
This review discusses current bottlenecks in making CRISPR-Cas9-mediated genome editing a therapeutic reality and it outlines recent strategies that aim to overcome these hurdles as well as the scope of current clinical trials that pioneer the medical translation of CRISPR-Cas9. Additionally, this review outlines the specifics of disease-modifying gene editing in recessive versus dominant genetic diseases with the focus on genetic myopathies that are exemplified by Duchenne muscular dystrophy and myotonic dystrophies.
Topics: Animals; CRISPR-Cas Systems; Gene Editing; Genetic Therapy; Humans; Muscular Dystrophy, Duchenne; Myotonic Dystrophy
PubMed: 30613384
DOI: 10.12688/f1000research.16106.1 -
Neuroepidemiology 2022Myotonic dystrophy (DM), the most common muscular dystrophy in adults, is a group of autosomal inherited neuromuscular disorders characterized by progressive muscle... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Myotonic dystrophy (DM), the most common muscular dystrophy in adults, is a group of autosomal inherited neuromuscular disorders characterized by progressive muscle weakness, myotonia, and cardiac conduction abnormalities. Due to the different gene mutations, DM has been subclassified into DM type 1 (DM1) and type 2 (DM2). However, the prevalence studies on DM and its subtypes are insufficient.
METHODS
The PubMed (1966-2022), MEDLINE (1950-2022), Web of Science (1864-2022), and Cochrane Library (2022) databases were searched for original research articles published in English. The quality of the included studies was assessed by a checklist adapted from Strengthening the Reporting of Observational studies in Epidemiology. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using the random-effects model. Heterogeneity was assessed using the Cochrane Q statistic and the I2 statistic.
RESULTS
A total of 17 studies were included in the systematic review and meta-analysis. Of the 17 studies evaluated, 14 studies were considered medium quality, 2 studies were considered high quality, and 1 study was considered low quality. The global prevalence of DM varied widely from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM was 9.99 cases (95% CI: 5.62-15.53) per 100,000. The pooled estimate of the prevalence of DM1 was 9.27 cases (95% CI: 4.73-15.21) per 100,000, ranging from 0.37 to 36.29 cases per 100,000. The pooled estimate of the prevalence of DM2 was 2.29 cases (95% CI: 0.17-6.53) per 100,000, ranging from 0.00 to 24.00 cases per 100,000.
CONCLUSION
Our study provided accurate estimates of the prevalence of DM. The high heterogeneity and the lack of high-quality studies highlight the need to conduct higher quality studies on orphan diseases.
Topics: Adult; Humans; Myotonic Dystrophy; Prevalence
PubMed: 35483324
DOI: 10.1159/000524734 -
International Journal of Molecular... Nov 2022Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3' UTR of the myotonic dystrophy protein kinase ()... (Review)
Review
Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3' UTR of the myotonic dystrophy protein kinase () gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.
Topics: Mice; Humans; Animals; Myotonic Dystrophy; Myotonin-Protein Kinase; Oligonucleotides, Antisense; Mice, Transgenic; Oligonucleotides; 3' Untranslated Regions; Trinucleotide Repeat Expansion
PubMed: 36362145
DOI: 10.3390/ijms232113359