Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 7.072
Filtrar
1.
Skelet Muscle ; 13(1): 1, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609344

RESUMO

BACKGROUND: The dystrophin-glycoprotein complex (DGC) is a critical adhesion complex of the muscle cell membrane, providing a mechanical link between the extracellular matrix (ECM) and the cortical cytoskeleton that stabilizes the sarcolemma during repeated muscle contractions. One integral component of the DGC is the transmembrane protein, sarcospan (SSPN). Overexpression of SSPN in the skeletal muscle of mdx mice (murine model of DMD) restores muscle fiber attachment to the ECM in part through an associated increase in utrophin and integrin adhesion complexes at the cell membrane, protecting the muscle from contraction-induced injury. In this study, we utilized transcriptomic and ECM protein-optimized proteomics data sets from wild-type, mdx, and mdx transgenic (mdxTG) skeletal muscle tissues to identify pathways and proteins driving the compensatory action of SSPN overexpression. METHODS: The tibialis anterior and quadriceps muscles were isolated from wild-type, mdx, and mdxTG mice and subjected to bulk RNA-Seq and global proteomics analysis using methods to enhance capture of ECM proteins. Data sets were further analyzed through the ingenuity pathway analysis (QIAGEN) and integrative gene set enrichment to identify candidate networks, signaling pathways, and upstream regulators. RESULTS: Through our multi-omics approach, we identified 3 classes of differentially expressed genes and proteins in mdxTG muscle, including those that were (1) unrestored (significantly different from wild type, but not from mdx), (2) restored (significantly different from mdx, but not from wild type), and (3) compensatory (significantly different from both wild type and mdx). We identified signaling pathways that may contribute to the rescue phenotype, most notably cytoskeleton and ECM organization pathways. ECM-optimized proteomics revealed an increased abundance of collagens II, V, and XI, along with ß-spectrin in mdxTG samples. Using ingenuity pathway analysis, we identified upstream regulators that are computationally predicted to drive compensatory changes, revealing a possible mechanism of SSPN rescue through a rewiring of cell-ECM bidirectional communication. We found that SSPN overexpression results in upregulation of key signaling molecules associated with regulation of cytoskeleton organization and mechanotransduction, including Yap1, Sox9, Rho, RAC, and Wnt. CONCLUSIONS: Our findings indicate that SSPN overexpression rescues dystrophin deficiency partially through mechanotransduction signaling cascades mediated through components of the ECM and the cortical cytoskeleton.


Assuntos
Distrofina , Distrofia Muscular de Duchenne , Camundongos , Animais , Distrofina/genética , Distrofina/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Mecanotransdução Celular , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Citoesqueleto/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo
2.
Proc Natl Acad Sci U S A ; 120(2): e2206324120, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36595689

RESUMO

Dystrophin is essential for muscle health: its sarcolemmal absence causes the fatal, X-linked condition, Duchenne muscular dystrophy (DMD). However, its normal, spatial organization remains poorly understood, which hinders the interpretation of efficacy of its therapeutic restoration. Using female reporter mice heterozygous for fluorescently tagged dystrophin (DmdEGFP), we here reveal that dystrophin distribution is unexpectedly compartmentalized, being restricted to myonuclear-defined sarcolemmal territories extending ~80 µm, which we called "basal sarcolemmal dystrophin units (BSDUs)." These territories were further specialized at myotendinous junctions, where both Dmd transcripts and dystrophin protein were enriched. Genome-level correction in X-linked muscular dystrophy mice via CRISPR/Cas9 gene editing restored a mosaic of separated dystrophin domains, whereas transcript-level Dmd correction, following treatment with tricyclo-DNA antisense oligonucleotides, restored dystrophin initially at junctions before extending along the entire fiber-with levels ~2% sufficient to moderate the dystrophic process. We conclude that widespread restoration of fiber dystrophin is likely critical for therapeutic success in DMD, perhaps most importantly, at muscle-tendon junctions.


Assuntos
Distrofina , Distrofia Muscular de Duchenne , Feminino , Camundongos , Animais , Distrofina/genética , Distrofina/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Distrofia Muscular de Duchenne/metabolismo , Músculos/metabolismo , Edição de Genes , Resultado do Tratamento , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Modelos Animais de Doenças
3.
Sci Rep ; 13(1): 179, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604563

RESUMO

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder manifesting in early childhood with progressive muscular weakness and atrophy, and resulting in early loss of ambulation. The collection and evaluation of epidemiological data for this disease is crucial for an early diagnosis and disease management. In Germany, data are collected via the TREAT-NMD DMD patient registry ( www.dmd-register.de ). In contrast, data collection in Austria has not yet been performed systematically. For collecting data from Austrian DMD patients, an online survey of the patient's caregivers was conducted. Data of 57 patients were collected entailing initial symptoms, diagnosis and therapeutic measures. Comparable data has been collected for Germany via the TREAT-NMD DMD patient registry. 57 DMD patients aged 4-34 years completed the Austrian survey. On average, first symptoms of the disease appeared at the age of 3.1 years. As the most frequent first symptom, 46% of the patients described problems in climbing stairs. In 40% of the patients, DMD was diagnosed early due to an accidentally detected hyperCKemia in infancy or early childhood. Corticosteroids represented the main therapeutic option in our cohort. At the time of the survey, only 52% of the patients were treated with corticosteroids. Patients from Germany reported that first symptoms appeared at the age of 3.06 years. Diagnosis was established by genetic testing or muscle biopsy. 47% of the patients were treated with corticosteroids. Time between first symptoms and diagnosis was 7 months in Austria, and 4.7 months in Germany, respectively. Compared to earlier international studies, the Austrian data show encouraging results regarding earlier start of corticosteroid therapy in a larger percentage of patients. Austrian and German data show a trend towards an earlier diagnosis of DMD, while the age at symptom onset was similar to previous studies. The collection and evaluation of epidemiological data of DMD patients is important and will hopefully contribute to accelerate DMD diagnosis and treatment access for the patients.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Pré-Escolar , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/epidemiologia , Áustria/epidemiologia , Corticosteroides/uso terapêutico , Testes Genéticos/métodos , Alemanha/epidemiologia
4.
J Pediatr Orthop ; 43(2): e163-e167, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36607927

RESUMO

BACKGROUND: Collagen VI-related myopathies with pathologic COL6A1, COL6A2, and COL6A3 variants manifest as a phenotypic continuum of rare disorders, including Bethlem myopathy (BM), characterized by early onset muscle weakness, proximal joint contractures, and distal joint laxity. Herein we discuss the concomitant orthopedic manifestations of BM, potential management strategies, and patient outcomes. METHODS: An IRB-approved retrospective cohort study (n=23) from 2 pediatric institutions with a confirmed diagnosis of BM. Charts were reviewed for demographic data, age of disease presentation and diagnosis, COL6 genotype, diagnosis method, ambulation status, need for assistance, musculoskeletal abnormalities, other systemic comorbidities, advanced imaging and screening diagnostics, previous surgical interventions, and progression of the disease. RESULTS: The mean age was 11.65 years (range 3 to 19 y). Mean age at initial presentation with symptoms was 4.18 years old, whereas diagnosis was delayed until 8.22 years old on average. Muscle weakness was the most common presenting symptom (65.2%), and 73.9% of patients required some use of assistive or mobility devices. Overall, 30.4% of patients were diagnosed with scoliosis; 57.1% required operative intervention for their scoliosis; 43.5% of patients had acetabular dysplasia; 10% required open reduction of a dislocated hip; 10% required closed reduction with hip spica application; 10% required bilateral periacetabular osteotomies for instability; 91.3% of patients developed foot and ankle deformities; 33.3% of patients underwent posteromedial-lateral equinovarus releases; 28.6% required an Achilles tendon lengthening, and 86.9% of patients had muscle tendon contractures, the most common locations being the ankle (55%) and elbow (40%). CONCLUSION: Although often less severe than other more common neuropathies and myopathies like Charcot-Marie-Tooth disease and Duchenne muscular dystrophy, BM does lead to progressive musculoskeletal deformity and disability. Its relative rarity makes it less familiar to providers and likely contributes to delays in diagnosis. Scoliosis, hip dysplasia, and equinus and varus ankle deformities are the most common musculoskeletal deformities. Physicians and surgeons should appropriately counsel patients and families about the clinical course of this disorder and the potential need for mobility assistance or surgical procedures. LEVEL OF EVIDENCE: III, Prognostic. study.


Assuntos
Contratura , Distrofia Muscular de Duchenne , Escoliose , Humanos , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Adulto , Estudos Retrospectivos , Mutação , Colágeno Tipo VI/genética , Contratura/etiologia , Contratura/cirurgia , Debilidade Muscular , Progressão da Doença
5.
Sensors (Basel) ; 23(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36679627

RESUMO

(1) Background: Duchenne (DMD) is a rare neuromuscular disease that progressively weakens muscles, which severely impairs gait capacity. The Six Minute-Walk Test (6MWT), which is commonly used to evaluate and monitor the disease's evolution, presents significant variability due to extrinsic factors such as patient motivation, fatigue, and learning effects. Therefore, there is a clear need for the establishment of precise clinical endpoints to measure patient mobility. (2) Methods: A novel score (6M+ and 2M+) is proposed, which is derived from the use of a new portable monitoring system capable of carrying out a complete gait analysis. The system includes several biomechanical sensors: a heart rate band, inertial measurement units, electromyography shorts, and plantar pressure insoles. The scores were obtained by processing the sensor signals and via gaussian-mixture clustering. (3) Results: The 6M+ and 2M+ scores were evaluated against the North Star Ambulatory Assessment (NSAA), the gold-standard for measuring DMD, and six- and two-minute distances. The 6M+ and 2M+ tests led to superior distances when tested against the NSAA. The 6M+ test and the 2M+ test in particular were the most correlated with age, suggesting that these scores better characterize the gait regressions in DMD. Additionally, the 2M+ test demonstrated an accuracy and stability similar to the 6M+ test. (4) Conclusions: The novel monitoring system described herein exhibited good usability with respect to functional testing in a clinical environment and demonstrated an improvement in the objectivity and reliability of monitoring the evolution of neuromuscular diseases.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Distrofia Muscular de Duchenne/diagnóstico , Fenômenos Biomecânicos , Reprodutibilidade dos Testes , Caminhada , Progressão da Doença
6.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675000

RESUMO

Water transport across the biological membranes is mediated by aquaporins (AQPs). AQP4 and AQP1 are the predominantly expressed AQPs in the skeletal muscle. Since the discovery of AQP4, several studies have highlighted reduced AQP4 levels in Duchenne muscular dystrophy (DMD) patients and mouse models, and other neuromuscular disorders (NMDs) such as sarcoglycanopathies and dysferlinopathies. AQP4 loss is attributed to the destabilizing dystrophin-associated protein complex (DAPC) in DMD leading to compromised water permeability in the skeletal muscle fibers. However, AQP4 knockout (KO) mice appear phenotypically normal. AQP4 ablation does not impair physical activity in mice but limits them from achieving the performance demonstrated by wild-type mice. AQP1 levels were found to be upregulated in DMD models and are thought to compensate for AQP4 loss. Several groups investigated the expression of other AQPs in the skeletal muscle; however, these findings remain controversial. In this review, we summarize the role of AQP4 with respect to skeletal muscle function and findings in NMDs as well as the implications from a clinical perspective.


Assuntos
Distrofia Muscular do Cíngulo dos Membros , Distrofia Muscular de Duchenne , Doenças Neuromusculares , Camundongos , Animais , Aquaporina 4/genética , Aquaporina 4/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular do Cíngulo dos Membros/metabolismo , Doenças Neuromusculares/metabolismo , Camundongos Knockout , Água/metabolismo , Distrofina/metabolismo
7.
Genes (Basel) ; 14(1)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36672942

RESUMO

Dysferlinopathy covers a spectrum of muscle disorder categorized by two major phenotypes, namely Miyoshi muscular dystrophy type 1 (MMD1, OMIM #254130) and limb-girdle muscular dystrophy autosomal recessive 2 (LGMDR2, OMIM #253601), and two minor symptoms, including asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT, OMIM #606768). We report the first Korean MMD1 misdiagnosed as Becker muscular dystrophy (BMD), which was caused by a combination of compound heterozygous c.663 + 1G > C and p.Trp992Arg of the DYSF gene. A 70-year-old male previously diagnosed with BMD was admitted for genetic counseling. Since he was clinically suspected to have dysferlinopathy but not BMD, targeted panel sequencing was performed to discover the potential hereditary cause of the suspected muscular dystrophy in the proband. Consequently, two pathogenic single nucleotide variants of the DYSF gene, c.663 + 1G > C (rs398123800) and p.Trp992Arg (rs750028300), associated with dysferlinopathy were identified. These variants were previously reported with variant allele frequencies of 0.000455 (c.663 + 1G > C) and 0.000455 (c.2974T > C; p.Trp992Arg) in the Korean population. This report emphasizes the need for common variant screening in the diagnostic algorithms of certain muscle disorders or gene panels with potential pathogenic effects and high rates of recurrent variants.


Assuntos
Miopatias Distais , Distrofia Muscular de Duchenne , Masculino , Humanos , Miopatias Distais/patologia , Disferlina , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Proteínas de Membrana/genética , Proteínas Musculares/genética , Erros de Diagnóstico
8.
Genes (Basel) ; 14(1)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36672955

RESUMO

Dystrophinopathies are X-linked recessive muscle disorders caused by mutations in the dystrophin (DMD) gene that include deletions, duplications, and point mutations. Correct diagnosis is important for providing adequate patient care and family planning, especially at this time when mutation-specific therapies are available. We report a large single-centre study on the spectrum of DMD gene variants observed in 750 patients analyzed for suspected Duchenne (DMD) or Becker (BMD) muscular dystrophy, over the past 30 years, at the Cardiomyology and Medical Genetics of the University of Campania. We found 534 (71.21%) large deletions, 73 (9.73%) large duplications, and 112 (14.93%) point mutations, of which 44 (5.9%) were small ins/del causing frame-shifts, 57 (7.6%) nonsense mutations, 8 (1.1%) splice site and 3 (0.4%) intronic mutations, and 31 (4.13%) non mutations. Moreover, we report the prevalence of the different types of mutations in patients with DMD and BMD according to their decade of birth, from 1930 to 2020, and correlate the data to the different techniques used over the years. In the most recent decades, we observed an apparent increase in the prevalence of point mutations, probably due to the use of Next-Generation Sequencing (NGS). In conclusion, in southern Italy, deletions are the most frequent variation observed in DMD and BMD patients followed by point mutations and duplications, as elsewhere in the world. NGS was useful to identify point mutations in cases of strong suspicion of DMD/BMD negative on deletions/duplications analyses. In the era of personalized medicine and availability of new causative therapies, a collective effort is necessary to enable DMD and BMD patients to have timely genetic diagnoses and avoid late implementation of standard of care and late initiation of appropriate treatment.


Assuntos
Distrofina , Distrofia Muscular de Duchenne , Humanos , Distrofina/genética , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Estudos Retrospectivos , Éxons , Mutação
9.
Sci Transl Med ; 15(677): eabo1815, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599002

RESUMO

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by the absence of dystrophin, a membrane-stabilizing protein encoded by the DMD gene. Although mouse models of DMD provide insight into the potential of a corrective therapy, data from genetically homologous large animals, such as the dystrophin-deficient golden retriever muscular dystrophy (GRMD) model, may more readily translate to humans. To evaluate the clinical translatability of an adeno-associated virus serotype 9 vector (AAV9)-microdystrophin (µDys5) construct, we performed a blinded, placebo-controlled study in which 12 GRMD dogs were divided among four dose groups [control, 1 × 1013 vector genomes per kilogram (vg/kg), 1 × 1014 vg/kg, and 2 × 1014 vg/kg; n = 3 each], treated intravenously at 3 months of age with a canine codon-optimized microdystrophin construct, rAAV9-CK8e-c-µDys5, and followed for 90 days after dosing. All dogs received prednisone (1 milligram/kilogram) for a total of 5 weeks from day -7 through day 28. We observed dose-dependent increases in tissue vector genome copy numbers; µDys5 protein in multiple appendicular muscles, the diaphragm, and heart; limb and respiratory muscle functional improvement; and reduction of histopathologic lesions. As expected, given that a truncated dystrophin protein was generated, phenotypic test results and histopathologic lesions did not fully normalize. All administrations were well tolerated, and adverse events were not seen. These data suggest that systemically administered AAV-microdystrophin may be dosed safely and could provide therapeutic benefit for patients with DMD.


Assuntos
Distrofia Muscular Animal , Distrofia Muscular de Duchenne , Animais , Cães , Humanos , Recém-Nascido , Camundongos , Distrofina/genética , Distrofina/metabolismo , Terapia Genética , Coração , Músculo Esquelético/metabolismo , Músculos/metabolismo , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/terapia , Distrofia Muscular Animal/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia
10.
Methods Mol Biol ; 2587: 467-478, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36401044

RESUMO

In vivo testing of glucocorticoid steroids in dystrophic mice offers important insights in benefits and risks of those drugs in the pathological context of muscular dystrophy. Frequency of dosing changes the spectrum of glucocorticoid effects on muscle and metabolic homeostasis. Here, we describe a combination of non-invasive and invasive methods to quantitatively discriminate the specific effects of intermittent (once-weekly) versus mainstay (once-daily) regimens on muscle fibrosis, muscle function, and metabolic homeostasis in murine models of Duchenne and limb-girdle muscular dystrophies.


Assuntos
Distrofia Muscular do Cíngulo dos Membros , Distrofia Muscular de Duchenne , Camundongos , Animais , Glucocorticoides/farmacologia , Glucocorticoides/metabolismo , Modelos Animais de Doenças , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/patologia , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/patologia
11.
Stem Cell Res ; 66: 103004, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565681

RESUMO

Duchenne muscular dystrophy (DMD), originating from the lack of functional dystrophin, clinically manifests as devastating disease of skeletal muscles with progressive cardiac involvement. HMOX1 promoter polymorphism may reflect different activity of heme oxygenase-1 (HO-1) that may be critical for DMD progression. Here we generated human induced pluripotent stem cell (hiPSC) lines from healthy donors-derived peripheral blood mononuclear cells with different variants of HMOX1 promoter (GT repeats), and engineered by CRISPR/Cas9-mediated deletion of exon 50 of DMD gene. Such in vitro model could add to molecular understanding of DMD and verify the prognostic value of HMOX1 promoter polymorphism.


Assuntos
Células-Tronco Pluripotentes Induzidas , Distrofia Muscular de Duchenne , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Sistemas CRISPR-Cas/genética , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Leucócitos Mononucleares/metabolismo , Distrofina/genética , Distrofina/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Éxons/genética
12.
J Neuromuscul Dis ; 10(1): 67-79, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36565131

RESUMO

BACKGROUND: Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited. OBJECTIVE: Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD. METHODS: Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models. RESULTS: This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p < 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p < 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p < 0.05 vs. no steroids). CONCLUSIONS: Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.


Assuntos
Distrofia Muscular de Duchenne , Qualidade de Vida , Masculino , Humanos , Adolescente , Prednisona/uso terapêutico , Volume Sistólico , Estudos Longitudinais , Função Ventricular Esquerda , Progressão da Doença
13.
Int J Exp Pathol ; 104(1): 4-12, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565155

RESUMO

There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from mdx mice. Dystrophic muscle cells were treated with Idebenone (0.05 µM) for 24 h. The untreated mdx muscle cells were used as controls. The MTT assay showed that Idebenone did not have a cytotoxic effect on the dystrophic muscle cells. The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2 O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells. These outcomes supported the use of Idebenone as a protective agent against oxidative stress and related signalling mechanisms involved in dystrophinopathies, such as DMD.


Assuntos
Músculo Esquelético , Distrofia Muscular de Duchenne , Animais , Camundongos , Camundongos Endogâmicos mdx , Músculo Esquelético/metabolismo , Cálcio/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Estresse Oxidativo , Inflamação/metabolismo , Células Musculares/metabolismo , Células Musculares/patologia
14.
Int J Exp Pathol ; 104(1): 13-22, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36565167

RESUMO

Duchenne muscular dystrophy (DMD) is the most severe and frequent form of muscular dystrophy. The mdx mouse is one of the most widely used experimental models to understand aspects of the biology of dystrophic skeletal muscles and the mechanisms of DMD. Oxidative stress and apoptosis are present in early stages of the disease in mdx mice. The high production of reactive oxygen species (ROS) causes activation of apoptotic death regulatory proteins due to DNA damage and breakdown of nuclear and mitochondrial membranes. The quadriceps (QUA) muscle of the mdx mouse is a good tool to study oxidative events. Previous studies have demonstrated that cilostazol exerts an anti-oxidant effect by decreasing the production of reactive oxygen species (ROS). The present study aimed to evaluate the ability of cilostazol to modulate oxidative stress and apoptosis in the QUA muscle of mdx mice. Fourteen-day-old mdx mice received cilostazol or saline for 14 days. C57BL/10 mice were used as a control. In the QUA muscle of mdx mice, cilostazol treatment decreased ROS production (-74%), the number of lipofuscin granules (-47%), lipid peroxidation (-11%), and the number of apoptotic cells (-66%). Thus cilostazol showed anti-oxidant and anti-apoptotic action in the QUA muscle of mdx mice.


Assuntos
Distrofia Muscular de Duchenne , Músculo Quadríceps , Camundongos , Animais , Camundongos Endogâmicos mdx , Espécies Reativas de Oxigênio/metabolismo , Cilostazol/farmacologia , Cilostazol/metabolismo , Músculo Quadríceps/metabolismo , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/tratamento farmacológico , Estresse Oxidativo , Apoptose
15.
Disabil Rehabil ; 44(23): 7023-7029, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34546805

RESUMO

AIM: Few studies have characterised the relationship between disease and gait function in children and young people with rare neuromuscular disorders (NMDs). This study aimed to describe the relationship between disease and gait in a large paediatric cohort from a neuromuscular outpatient clinic. METHODS: A prospective, cross-sectional study of gait in independently ambulant children and young people aged 4-21 years with a clinical or genetically confirmed NMD. Participants traversed an electronic walkway barefoot and in footwear at self-selected and fast pace. Analysis of disease included a typically developing (TD) reference group. RESULTS: A sample of 113 participants with NMD, mean age 9.5 years (SD 3.1), 28% female, grouped into nine diagnostic subgroups. Eighty percent reported limitations to functional mobility. Children with NMD walked slower, with a shorter and wider step compared to a TD reference group, with moderate to large effect sizes for each of these gait parameters indicative of the clinical significance of these gait deviations. Children with Duchenne muscular dystrophy (DMD) walked slowest with a markedly wide gait pattern. Footwear had little overall effect on gait in children with NMDs. All children could accelerate over short distances. CONCLUSIONS: Gait, notably speed, step length, and width are clinically significant biomarkers of disease in paediatric NMDs, affording objective functional measures in clinical settings and research.Implications for rehabilitationGait should be considered a functional biomarker of disease in children and young people with neuromuscular disorders (NMDs).Comparison of gait in a paediatric neuromuscular cohort indicates that children with Duchenne muscular dystrophy (DMD) walk slowest with a shorter step length and a wider step width which increases with age and disease progression.Measurement of gait speed is a simple, pragmatic tool to monitor disease progression in the outpatient clinical environment and relates to everyday function.In clinical research, gait can be measured as a functional outcome to demonstrate change from disease-modifying interventions and treatments in NMDs.


Assuntos
Distrofia Muscular de Duchenne , Criança , Humanos , Feminino , Adolescente , Masculino , Estudos Transversais , Estudos Prospectivos , Marcha , Progressão da Doença
16.
J UOEH ; 44(4): 323-330, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36464306

RESUMO

We aimed to clarify the effect of aging on trabecular bone volume and trabecular bone microstructure in a rat model of Duchenne muscular dystrophy (DMD). Six rats each of wild type (WT) and DMD model at 15 weeks of age, and 4 rats each at 30 weeks of age, were analyzed by dual energy X-ray absorptiometry and by micro-CT for analysis of trabecular and cortical bone of the femur. Bone mineral density was significantly lower in the DMD group than in the WT group at both 15 and 30 weeks of age. Micro-CT showed that trabecular bone volume and number were not significantly different between the two groups at 15 weeks, but at 30 weeks both were significantly lower in the DMD group than in the WT group. Connectivity density and structure model index were not significantly different between the two groups at 15 weeks, but at 30 weeks they differed significantly. No significant differences between the WT and DMD groups in cortical thickness and cortical area were evident at both 15 and 30 weeks. In conclusion, trabecular bone volume is significantly reduced, with deteriorated microstructure, with aging in a rat model of DMD.


Assuntos
Distrofia Muscular de Duchenne , Ratos , Animais , Distrofia Muscular de Duchenne/diagnóstico por imagem , Osso Esponjoso/diagnóstico por imagem , Envelhecimento
17.
Artigo em Inglês | MEDLINE | ID: mdl-36497753

RESUMO

Progressive, irreversible muscle weakness is the leading symptom of Duchenne muscular dystrophy (DMD), often resulting in death from respiratory muscle failure. Little is known about the relationship between the functioning of the respiratory system and the hand grip-a function which remains long preserved. This study aimed to investigate the interdependence between muscle strength and the function of both hand grip and the respiratory system in patients with DMD. MATERIALS AND METHOD: The study included cohort patients, aged 6-17, with DMD, recruited from the Rare Disease Centre, Gdansk, Poland. Clinical status (Vignos scale, Brook scale), pulmonary function (respiratory muscle strength-MIP, MEP); spirometry (FEV1; FVC), as well as upper limb function (performance of the upper limb-PUL 2.0) and hand grip strength (HGS) (hand-held dynamometer) were evaluated in all participants. RESULTS: Finally, 53 boys (mean age 11.41 ± 3.70 years, 25 non-ambulant) were included. Each of the participants presented a lower %pv of MIP (48.11 ± 27), MEP (38.11 ± 22), PUL (75.64 ± 27), and HGS (33.28 ± 18). There were differences between the ambulatory and non-ambulatory groups in values of MIP, MEP, FVC, PUL, HGS (p < 0.001 for all), and FEV1 (p < 0.013). There were correlations between PUL, HGS, and MIP (R = 0.56; R = 0.61, p < 0.001 both), MEP (R = 0.59; R = 0.62, p < 0.001), FVC (R = 0.77; R = 0.77, p < 0.001), and FEV1 (R = 0.77; R = 0.79; p < 0.001). These correlations were found for all participants, but non-ambulatory patients presented stronger relationships. CONCLUSIONS: 1. The pulmonary and upper limb functions were within the normal range in ambulatory and low in non-ambulatory patients with DMD, but the muscle strength of both systems was low, regardless of the stage of the disease. 2. There seems to be an interdependence between the respiratory system and upper limb strength in terms of muscle strength and function in DMD patients, which is stronger in non-ambulatory patients. This may be the basis for the creation of a new personalized plan in rehabilitation-the simultaneous rehabilitation of the respiratory and upper limb muscles. Further studies on this theory should be conducted.


Assuntos
Distrofia Muscular de Duchenne , Masculino , Humanos , Criança , Adolescente , Força da Mão , Extremidade Superior , Músculos Respiratórios , Debilidade Muscular , Pulmão
18.
Front Immunol ; 13: 1049076, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36569900

RESUMO

Background: Duchenne muscular dystrophy (DMD) is the most common inherited human myopathy. Typically, the secondary process involving severe inflammation and necrosis exacerbate disease progression. Previously, we reported that the NLRP3 inflammasome complex plays a crucial role in this disorder. Moreover, pyroptosis, a form of programmed necrotic cell death, is triggered by NLRP3 via gasdermin D (GSDMD). So far, pyroptosis has never been described either in healthy muscle or in dystrophic muscle. The aim of this study was to unravel the role of NLRP3 inflammasome in DMD and explore a potentially promising treatment with MCC950 that selectively inhibits NLRP3. Methods: Four-week-old mdx mice (n=6 per group) were orally treated for 2 months with MCC950 (mdx-T), a highly potent, specific, small-molecule inhibitor of NLRP3, and compared with untreated (mdx) and wild-type (WT) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of DMD human myotubes. Results: After MCC950 treatment, mdx mice exhibited a significant reduction of inflammation, macrophage infiltration and oxidative stress (-20 to -65%, P<0.05 vs untreated mdx). Mdx-T mice displayed considerably less myonecrosis (-54%, P<0.05 vs mdx) and fibrosis (-75%, P<0.01 vs mdx). Moreover, a more mature myofibre phenotype, characterized by larger-sized fibres and higher expression of mature myosin heavy chains 1 and 7 was observed. Mdx-T also exhibited enhanced force and resistance to fatigue (+20 to 60%, P<0.05 or less). These beneficial effects resulted from MCC950 inhibition of both active caspase-1 (-46%, P=0.075) and cleaved gasdermin D (N-GSDMD) (-42% in medium-sized-fibres, P<0.001). Finally, the anti-inflammatory action and the anti-pyroptotic effect of MCC950 were also recapitulated in DMD human myotubes. Conclusion: Specific inhibition of the NLRP3 inflammasome can significantly attenuate the dystrophic phenotype. A novel finding of this study is the overactivation of GSDMD, which is hampered by MCC950. This ultimately leads to less inflammation and pyroptosis and to a better muscle maturation and function. Targeting NLRP3 might lead to an effective therapeutic approach for a better management of DMD.


Assuntos
Distrofia Muscular de Duchenne , Humanos , Animais , Camundongos , Distrofia Muscular de Duchenne/tratamento farmacológico , Inflamassomos/metabolismo , Camundongos Endogâmicos mdx , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Músculo Esquelético/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Inflamação/metabolismo
20.
Continuum (Minneap Minn) ; 28(6): 1678-1697, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36537975

RESUMO

PURPOSE OF REVIEW: This article reviews the history, epidemiology, genetics, clinical presentation, multidisciplinary management, and established and emerging therapies for the dystrophinopathies. RECENT FINDINGS: The multidisciplinary care of individuals with dystrophinopathies continues to improve in many ways, including early surveillance and implementation of respiratory, cardiac, and orthopedic health management. The era of genetic therapeutics has altered the treatment landscape in neuromuscular disorders, including the dystrophinopathies. SUMMARY: The dystrophinopathies are a spectrum of X-linked genetic disorders characterized by childhood-onset progressive weakness and variable cardiac and cognitive involvement. Corticosteroids are the mainstay of therapy to slow disease progression. Additional strategies for disease amelioration and dystrophin restoration, including gene replacement therapy, are under investigation.


Assuntos
Corticosteroides , Distrofia Muscular de Duchenne , Humanos , Criança , Corticosteroides/uso terapêutico , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...