Altered β‐adrenergic response in mice lacking myotonic dystrophy protein kinase

Llagostera, Esther; López, María Jesúsá Álvarez; Scimia, Cecilia; Catalucci, Daniele; Párrizas, Marcelina; Ruiz‐Lozano, Pilar; Kaliman, Perla

doi:10.1002/mus.22256

Cited by 3 publications

(7 citation statements)

References 19 publications

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“…As our analysis indicates, this regulation might include cis -acting regulatory elements in dissimilar neighboring genes, such as a muscle-specific enhancer for muscle-related upregulation of DMPK in the testis-specific RSPH6A gene. The tissue-specific epigenetics of DMPK that we have described is consistent with the importance of this gene to myoblast differentiation [ 3 ], insulin signaling in skeletal and cardiac muscles [ 4 ], regulation of ion channels in skeletal muscle [ 7 , 23 ], cardiac conduction [ 9 ], and with the much higher levels of DMPK protein in heart and skeletal muscle relative to most other tissues [ 79 ]. Last, the tissue-specific epigenetics in and around DMPK and the G-quadruplex motifs near the DM1-linked CTG repeat at the 3′ end of DMPK are likely to be important in understanding disease mechanisms for this highly lethal and debilitating disease.…”

Section: Discussionsupporting

confidence: 72%

“…The most prominent roles of DMPK protein in normal tissues are in skeletal and heart muscle. Its functions include regulating calcium ion homeostasis in myotubes (Mt) [ 6 ], sodium ion-channel gating in skeletal muscle tissue [ 7 ], promoting Mt formation from myoblasts (Mb) [ 8 ], protecting against age-related muscle weakness [ 1 ], protecting membrane-bound cardiac β-adrenergic receptors [ 9 ] and facilitating atrioventricular conduction [ 10 ]. Although DMPK is expressed in diverse tissues, skeletal muscle, cardiac muscle and certain smooth muscles display much higher steady-state levels than most other tissues [ 11–14 ].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetics of the Myotonic Dystrophy-Associated DMPK gene neighborhood

2016

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Aim:Identify epigenetic marks in the vicinity of DMPK (linked to myotonic dystrophy, DM1) that help explain tissue-specific differences in its expression.Materials & methods:At DMPK and its flanking genes (DMWD, SIX5, BHMG1 and RSPH6A), we analyzed many epigenetic and transcription profiles from myoblasts, myotubes, skeletal muscle, heart and 30 nonmuscle samples.Results:In the DMPK gene neighborhood, muscle-associated DNA hypermethylation and hypomethylation, enhancer chromatin, and CTCF binding were seen. Myogenic DMPK hypermethylation correlated with high expression and decreased alternative promoter usage. Testis/sperm hypomethylation of BHMG1 and RSPH6A was associated with testis-specific expression. G-quadruplex (G4) motifs and sperm-specific hypomethylation were found near the DM1-linked CTG repeats within DMPK.Conclusion:Tissue-specific epigenetic features in DMPK and neighboring genes help regulate its expression. G4 motifs in DMPK DNA and RNA might contribute to DM1 pathology.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Epigenetics of the Myotonic Dystrophy-Associated DMPK gene neighborhood

2016

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“…Further, 227 studies remained for the full-text analysis, in which 181 did not present relevant data for the aim of this review and four did not use DM1 biological models. Finally, 41 studies [ 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ] were included in the present systematic review. The details of the screening process can be found in the PRISMA flow diagram in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Transgenic mice expressing the human skeletal actin gene with 250 CTG repeats (HSALR) was the most used mice model to study protein phosphorylation in DM1 (n = 4) [ 26 , 33 , 43 , 44 ] ( Figure 2 B). Further, the DMSXL mice (n = 3) [ 53 , 54 , 55 ], Dmpk knockout mice (n = 2) [ 38 , 39 ], and inducible transgenic mice with expanded repeats induced by Tamoxifen (TAM) (n = 2) [ 37 , 52 ] were also among the most used DM1 mice models ( Figure 2 B). Concerning the human samples, in most studies skeletal muscle biopsies were used (n = 15) [ 26 , 28 , 29 , 32 , 33 , 34 , 40 , 45 , 46 , 50 , 57 , 58 , 59 , 61 , 62 ], followed by primary myoblasts (n = 7) [ 24 , 31 , 33 , 47 , 49 , 50 , 53 ] and primary myotubes (n = 4) [ 25 , 28 , 47 , 49 ] ( Figure 2 C).…”

Section: Resultsmentioning

confidence: 99%

Protein Phosphorylation Alterations in Myotonic Dystrophy Type 1: A Systematic Review

Costa

Cruz

Martins

et al. 2023

IJMS

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Among the most common muscular dystrophies in adults is Myotonic Dystrophy type 1 (DM1), an autosomal dominant disorder characterized by myotonia, muscle wasting and weakness, and multisystemic dysfunctions. This disorder is caused by an abnormal expansion of the CTG triplet at the DMPK gene that, when transcribed to expanded mRNA, can lead to RNA toxic gain of function, alternative splicing impairments, and dysfunction of different signaling pathways, many regulated by protein phosphorylation. In order to deeply characterize the protein phosphorylation alterations in DM1, a systematic review was conducted through PubMed and Web of Science databases. From a total of 962 articles screened, 41 were included for qualitative analysis, where we retrieved information about total and phosphorylated levels of protein kinases, protein phosphatases, and phosphoproteins in DM1 human samples and animal and cell models. Twenty-nine kinases, 3 phosphatases, and 17 phosphoproteins were reported altered in DM1. Signaling pathways that regulate cell functions such as glucose metabolism, cell cycle, myogenesis, and apoptosis were impaired, as seen by significant alterations to pathways such as AKT/mTOR, MEK/ERK, PKC/CUGBP1, AMPK, and others in DM1 samples. This explains the complexity of DM1 and its different manifestations and symptoms, such as increased insulin resistance and cancer risk. Further studies can be done to complement and explore in detail specific pathways and how their regulation is altered in DM1, to find what key phosphorylation alterations are responsible for these manifestations, and ultimately to find therapeutic targets for future treatments.

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“…Conduction defects, like those of DM1 patients, such as age-dependent first-degree atrioventricular blocks, have been reported in heterozygous adult Dmpk knock-out mice [ 158 , 159 ]. Another study showed that there are fewer β1-adrenergic receptors at the cardiac sarcolemma of Dmpk knock-out mice, suggesting that DMPK protein plays a role in the regulation of membrane trafficking [ 160 ]. Dmpk knockout mice have also been reported to feature increased CELF phosphorylation and nuclear localization [ 161 ].…”

Section: Safety and Tolerability Of Dmpk -Targetin...mentioning

confidence: 99%

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

Serres-Bérard

Benichou

Jauvin

et al. 2022

IJMS

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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 (DMPK) 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.

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Altered β‐adrenergic response in mice lacking myotonic dystrophy protein kinase

Cited by 3 publications

References 19 publications

Epigenetics of the Myotonic Dystrophy-Associated DMPK gene neighborhood

Epigenetics of the Myotonic Dystrophy-Associated DMPK gene neighborhood

Protein Phosphorylation Alterations in Myotonic Dystrophy Type 1: A Systematic Review

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1

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