Dataset Information

Circulating Nrf2, Glutathione, and Malondialdehyde Correlate with Disease Severity in Duchenne Muscular Dystrophy.

ABSTRACT: Oxidative stress (OS) plays an essential role in the pathophysiology of Duchenne muscular dystrophy (DMD). However, the actors that regulate OS need to be better studied. We aimed to evaluate whether NFE2-like bZIP transcription factor 2 (Nrf2), glutathione, malondialdehyde (MDA), and protein carbonyl concentrations change according to the disease severity in DMD patients. Moreover, we assessed whether OS correlated with muscle injury, clinical characteristics, physical activity, and antioxidant food consumption (AFC). A total of 28 DMD patients participated in this study. OS markers, metabolic indicators, and enzymatic markers of muscle injury were measured in circulation. Muscle injury was measured with clinical scales, and physical activity and AFC were evaluated with questionnaires. Nrf2 concentration was lower (p ≤ 0.01), and malondialdehyde concentration was higher (p < 0.05) in non-ambulatory patients than in ambulatory patients. Nrf2 correlated with age (rho = -0.387), Vignos scale (rho = -0.328), GMFCS scale (rho = -0.399), and Brooke scale scores (rho = -0.371) (p < 0.05). MDA correlated with Vignos (rho = 0.317) and Brooke scale scores (rho = 0.414) (p ≤ 0.05). In conclusion, DMD patients with the worst muscle function had more significant oxidative damage and lower antioxidant function than DMD patients with better muscle function.

SUBMITTER: Almeida-Becerril T

PROVIDER: S-EPMC10135301 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

Circulating Nrf2, Glutathione, and Malondialdehyde Correlate with Disease Severity in Duchenne Muscular Dystrophy.

Almeida-Becerril Tomas T Rodríguez-Cruz Maricela M Villa-Morales Judith J Sánchez-Mendoza Christian Ricardo CR Galeazzi-Aguilar Jose Emilio JE

Antioxidants (Basel, Switzerland) 20230403 4

Oxidative stress (OS) plays an essential role in the pathophysiology of Duchenne muscular dystrophy (DMD). However, the actors that regulate OS need to be better studied. We aimed to evaluate whether NFE2-like bZIP transcription factor 2 (Nrf2), glutathione, malondialdehyde (MDA), and protein carbonyl concentrations change according to the disease severity in DMD patients. Moreover, we assessed whether OS correlated with muscle injury, clinical characteristics, physical activity, and antioxidant ...[more]

PMID: 37107246

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Project description:Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy (BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls. We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials. Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly the remaining muscle mass in DMD.

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

Circulating Nrf2, Glutathione, and Malondialdehyde Correlate with Disease Severity in Duchenne Muscular Dystrophy.

Publications

Circulating Nrf2, Glutathione, and Malondialdehyde Correlate with Disease Severity in Duchenne Muscular Dystrophy.

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