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Targeting Myotonic Dystrophy Type 1 with Metformin.

ABSTRACT: Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 patients. Metformin is a biguanide antidiabetic drug, with potential to delay aging at cellular and organismal levels. In DM1, different studies revealed that metformin rescues multiple phenotypes of the disease. This review provides an overview of recent findings describing metformin as a novel therapy to combat DM1 and their link with aging.

SUBMITTER: Garcia-Puga M

PROVIDER: S-EPMC8910924 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Targeting Myotonic Dystrophy Type 1 with Metformin.

García-Puga Mikel M Saenz-Antoñanzas Ander A Matheu Ander A López de Munain Adolfo A

International journal of molecular sciences 20220307 5

Myotonic dystrophy type 1 (DM1) is a multisystemic disorder of genetic origin. Progressive muscular weakness, atrophy and myotonia are its most prominent neuromuscular features, while additional clinical manifestations in multiple organs are also common. Overall, DM1 features resemble accelerated aging. There is currently no cure or specific treatment for myotonic dystrophy patients. However, in recent years a great effort has been made to identify potential new therapeutic strategies for DM1 pa ...[more]

PMID: 35270043

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Myotonic Dystrophy type 1 cells display impaired metabolism and mitochondrial dysfunction that are reversed by metformin.

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Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.

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Dynamic docking of small molecules targeting RNA CUG repeats causing myotonic dystrophy type 1.

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Disease burden of myotonic dystrophy type 1.

Project description:ObjectiveThe objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder.MethodsAdults with DM1 were recruited as part of the PhenoDM1 study from Newcastle University (Newcastle upon Tyne, UK). Disease burden data were recorded through the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Results were examined by sex and clinical variables [e.g. the six-minute walk test (6MWT), the Mini Mental State Examination, and estimated progenitor and modal allele CTG repeat length].ResultsOur sample consisted of 60 patients with DM1 (mean age: 45 years; 45% female). Muscle weakness and fatigue constituted the two most common disease manifestations, reported by 93% and 90% of patients, respectively, followed by muscle locking (73%). Most patients (> 55%) reported feeling anxious/worried, depressed, frustrated, and/or having low confidence/self-esteem, 23% and 33% indicated substantial impairment of daily and leisure activities, respectively, and 47% did not work as a consequence of the disease. Estimated progenitor CTG length corrected by age correlated surprisingly well with INQoL scores. Differences by sex were generally minor.ConclusionWe show that DM1 is associated with a substantial disease burden resulting in impairment across many different domains of patients' lives, emphasizing the need for a holistic approach to medical management. Our results also show that the INQoL records relevant information about patients with DM1, but that further investigation of the psychometric properties of the scale is needed for meaningful interpretation of instrument scores.

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Project description:Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system. Since microRNA (miRNA) expression is disrupted in Myotonic Dystrophy Type-1 and many other myopathies, miRNAs deregulation was studied in skeletal muscle biopsies of 13 DM2 patients and 13 controls. Eleven miRNAs were deregulated: 9 displayed higher levels compared to controls (miR-34a-5p, miR-34b-3p, miR-34c-5p, miR-146b-5p, miR-208a, miR-221-3p and miR-381), while 4 were decreased (miR-125b-5p, miR-193a-3p, miR-193b-3p and miR-378a-3p). To explore the relevance of DM2 miRNA deregulation, the predicted interactions between miRNA and mRNA were investigated. Global gene expression was analyzed in DM2 and controls and bioinformatic analysis identified more than 1,000 miRNA/mRNA interactions. Pathway and function analysis highlighted the involvement of the miRNA-deregulated mRNAs in multiple aspects of DM2 pathophysiology. In conclusion, the observed miRNA dysregulations may contribute to DM2 pathogenetic mechanisms.

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Overexpression of CUGBP1 in skeletal muscle from adult classic myotonic dystrophy type 1 but not from myotonic dystrophy type 2.

Project description:Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are progressive multisystemic disorders caused by similar mutations at two different genetic loci. The common key feature of DM pathogenesis is nuclear accumulation of mutant RNA which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of two RNA binding proteins, MBNL1 and CUGBP1. However, DM1 and DM2 show disease-specific features that make them clearly separate diseases suggesting that other cellular and molecular pathways may be involved. In this study we have analysed the histopathological, and biomolecular features of skeletal muscle biopsies from DM1 and DM2 patients in relation to presenting phenotypes to better define the molecular pathogenesis. Particularly, the expression of CUGBP1 protein has been examined to clarify if this factor may act as modifier of disease-specific manifestations in DM. The results indicate that the splicing and muscle pathological alterations observed are related to the clinical phenotype both in DM1 and in DM2 and that CUGBP1 seems to play a role in classic DM1 but not in DM2. In conclusion, our results indicate that multisystemic disease spectrum of DM pathologies may not be explained only by spliceopathy thus confirming that the molecular pathomechanism of DM is more complex than that actually suggested.

| S-EPMC3869793 | biostudies-literature

Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1.

Project description:PurposeRNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs' endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium.MethodsFECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA.ResultsFECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P < 0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients.ConclusionsFECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.

| S-EPMC6005624 | biostudies-literature

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