Dataset Information

The microRNA miR-133b functions to slow Duchenne muscular dystrophy pathogenesis.

ABSTRACT:

Key points

Impairment of muscle biogenesis contributes to the progression of Duchenne muscular dystrophy (DMD). As a muscle enriched microRNA that has been implicated in muscle biogenesis, the role of miR-133b in DMD remains unknown. To assess miR-133b function in DMD-affected skeletal muscles, we genetically ablated miR-133b in the mdx mouse model of DMD. We show that deletion of miR-133b exacerbates the dystrophic phenotype of DMD-afflicted skeletal muscle by dysregulating muscle stem cells involved in muscle biogenesis, in addition to affecting signalling pathways related to inflammation and fibrosis. Our results provide evidence that miR-133b may underlie DMD pathology by affecting the proliferation and differentiation of muscle stem cells.

Abstract

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle degeneration. No treatments are currently available to prevent the disease. While the muscle enriched microRNA miR-133b has been implicated in muscle biogenesis, its role in DMD remains unknown. To assess miR-133b function in DMD-affected skeletal muscles, we genetically ablated miR-133b in the mdx mouse model of DMD. In the absence of miR-133b, the tibialis anterior muscle of P30 mdx mice is smaller in size and exhibits a thickened interstitial space containing more mononucleated cells. Additional analysis revealed that miR-133b deletion influences muscle fibre regeneration, satellite cell proliferation and differentiation, and induces widespread transcriptomic changes in mdx muscle. These include known miR-133b targets as well as genes involved in cell proliferation and fibrosis. Altogether, our data demonstrate that skeletal muscles utilize miR-133b to mitigate the deleterious effects of DMD.

SUBMITTER: Taetzsch T

PROVIDER: S-EPMC8418193 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

The microRNA miR-133b functions to slow Duchenne muscular dystrophy pathogenesis.

Key points

Abstract

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