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1.
Neuromuscul Disord ; 32(4): 332-346, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35393236

RESUMO

Muscular dystrophies are a group of disorders that cause progressive muscle weakness. There is an increasing interest for the development of biomarkers for these disorders and specifically for Duchene Muscular Dystrophy. Limited research however, has been performed on the biomarkers' development for the most rare muscular dystrophies, like the Facioscapulohumeral Muscular Dystrophy, Limb-Girdle Muscular Dystrophy and Myotonic Dystrophy type 2. Here, we aimed to identify novel serum-based miRNA biomarkers for these rare muscular dystrophies, through high-throughput next-generation RNA sequencing. We identified many miRNAs that associate with muscular dystrophy patients compared to controls. Based on a series of selection criteria, the two best candidate miRNAs for each of these disorders were chosen and validated in a larger number of patients. Our results showed that miR-223-3p and miR-206 are promising serum-based biomarkers for Facioscapulohumeral Muscular Dystrophy type 1, miR-143-3p and miR-486-3p for Limb-Girdle Muscular Dystrophy type 2A whereas miR-363-3p and miR-25-3p associate with Myotonic Dystrophy type 2. Some of the identified miRNAs were significantly elevated in the serum of the patients compared to controls, whereas some others were lower. In conclusion, we provide new evidence that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies.


Assuntos
MicroRNAs , Distrofia Muscular do Cíngulo dos Membros , Distrofia Muscular Facioescapuloumeral , Distrofia Miotônica , Biomarcadores/sangue , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Distrofia Muscular do Cíngulo dos Membros/sangue , Distrofia Muscular do Cíngulo dos Membros/diagnóstico , Distrofia Muscular do Cíngulo dos Membros/genética , Distrofia Muscular Facioescapuloumeral/sangue , Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/genética , Distrofia Miotônica/sangue , Distrofia Miotônica/diagnóstico , Distrofia Miotônica/genética
2.
RNA Biol ; 19(1): 507-518, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35388741

RESUMO

Muscular dystrophies are a group of rare and severe inherited disorders mainly affecting the muscle tissue. Duchene Muscular Dystrophy, Myotonic Dystrophy types 1 and 2, Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy are some of the members of this family of disorders. In addition to the current diagnostic tools, there is an increasing interest for the development of novel non-invasive biomarkers for the diagnosis and monitoring of these diseases. miRNAs are small RNA molecules characterized by high stability in blood thus making them ideal biomarker candidates for various diseases. In this study, we present the first genome-wide next-generation small RNA sequencing in serum samples of five different types of muscular dystrophy patients and healthy individuals. We identified many small RNAs including miRNAs, lncRNAs, tRNAs, snoRNAs and snRNAs, that differentially discriminate the muscular dystrophy patients from the healthy individuals. Further analysis of the identified miRNAs showed that some miRNAs can distinguish the muscular dystrophy patients from controls and other miRNAs are specific to the type of muscular dystrophy. Bioinformatics analysis of the target genes for the most significant miRNAs and the biological role of these genes revealed different pathways that the dysregulated miRNAs are involved in each type of muscular dystrophy investigated. In conclusion, this study shows unique signatures of small RNAs circulating in five types of muscular dystrophy patients and provides a useful resource for future studies for the development of miRNA biomarkers in muscular dystrophies and for their involvement in the pathogenesis of the disorders.


Assuntos
MicroRNAs , Distrofias Musculares , Distrofia Miotônica , Biomarcadores , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , MicroRNAs/genética , Distrofias Musculares/diagnóstico , Distrofias Musculares/genética
3.
Mol Ther Methods Clin Dev ; 23: 169-183, 2021 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-34703840

RESUMO

Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy, primarily characterized by muscle wasting and weakness. Many biomarkers already exist in the rapidly developing biomarker research field that aim to improve patients' care. Limited work, however, has been performed on rare diseases, including DM1. We have previously shown that specific microRNAs (miRNAs) can be used as potential biomarkers for DM1 progression. In this report, we aimed to identify novel serum-based biomarkers for DM1 through high-throughput next-generation sequencing. A number of miRNAs were identified that are able to distinguish DM1 patients from healthy individuals. Two miRNAs were selected, and their association with the disease was validated in a larger panel of patients. Further investigation of miR-223-3p, miR-24-3p, and the four previously identified miRNAs, miR-1-3p, miR-133a-3p, miR-133b-3p, and miR-206-3p, showed elevated levels in a DM1 mouse model for all six miRNAs circulating in the serum compared to healthy controls. Importantly, the levels of miR-223-3p, but not the other five miRNAs, were found to be significantly downregulated in five skeletal muscles and heart tissues of DM1 mice compared to controls. This result provides significant evidence for its involvement in disease manifestation.

4.
J Cell Sci ; 128(19): 3631-45, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26272918

RESUMO

Twist-1 is mostly expressed during development and has been previously shown to control myogenesis. Because its regulation in muscle has not been fully exploited, the aim of this project was to identify micro (mi)RNAs in muscle that regulate Twist-1. miR-206, one of the most important muscle-specific miRNAs (myomiRs), was identified as a possible regulator of Twist-1 mRNA. Luciferase assays and transfections in human foetal myoblasts showed that Twist-1 is a direct target of miR-206 and that through this pathway muscle cell differentiation is promoted. We next investigated whether MyoD, a major myogenic transcription factor, regulates Twist-1 because it is known that MyoD induces expression of the miR-206 gene. We found that forced MyoD expression induced miR-206 upregulation and Twist-1 downregulation through binding to the miR-206 promoter, followed by increased muscle cell differentiation. Finally, experiments were performed in muscle cells from subjects with congenital myotonic dystrophy type 1, in which myoblasts fail to differentiate into myotubes. MyoD overexpression inhibited Twist-1 through miR-206 induction, which was followed by an increase in muscle cell differentiation. These results reveal a previously unidentified mechanism of myogenesis that might also play an important role in muscle disease.


Assuntos
MicroRNAs/genética , Proteína MyoD/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Imunoprecipitação da Cromatina , Humanos , Desenvolvimento Muscular/genética , Desenvolvimento Muscular/fisiologia , Proteína MyoD/genética , Mioblastos/citologia , Mioblastos/metabolismo
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