Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.
Ontology highlight
ABSTRACT:
SUBMITTER: Momma K
PROVIDER: S-EPMC3522649 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.
Momma Kazunari K Noguchi Satoru S Malicdan May Christine V MC Hayashi Yukiko K YK Minami Narihiro N Kamakura Keiko K Nonaka Ikuya I Nishino Ichizo I
PloS one 20121214 12
Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in D ...[more]
Similar Datasets
Project description:ObjectiveSporadic inclusion body myositis (sIBM) pathogenesis is unknown; however, rimmed vacuoles (RVs) are a constant feature. We propose to identify proteins that accumulate within RVs.MethodsRVs and intact myofibers were laser microdissected from skeletal muscle of 18 sIBM patients and analyzed by a sensitive mass spectrometry approach using label-free spectral count-based relative protein quantification. Whole exome sequencing was performed on 62 sIBM patients. Immunofluorescence was performed on patient and mouse skeletal muscle.ResultsA total of 213 proteins were enriched by >1.5 -fold in RVs compared to controls and included proteins previously reported to accumulate in sIBM tissue or when mutated cause myopathies with RVs. Proteins associated with protein folding and autophagy were the largest group represented. One autophagic adaptor protein not previously identified in sIBM was FYCO1. Rare missense coding FYCO1 variants were present in 11.3% of sIBM patients compared with 2.6% of controls (p = 0.003). FYCO1 colocalized at RVs with autophagic proteins such as MAP1LC3 and SQSTM1 in sIBM and other RV myopathies. One FYCO1 variant protein had reduced colocalization with MAP1LC3 when expressed in mouse muscle.InterpretationThis study used an unbiased proteomic approach to identify RV proteins in sIBM that included a novel protein involved in sIBM pathogenesis. FYCO1 accumulates at RVs, and rare missense variants in FYCO1 are overrepresented in sIBM patients. These FYCO1 variants may impair autophagic function, leading to RV formation in sIBM patient muscle. FYCO1 functionally connects autophagic and endocytic pathways, supporting the hypothesis that impaired endolysosomal degradation underlies the pathogenesis of sIBM. Ann Neurol 2017;81:227-239.
| S-EPMC5323275 | biostudies-literature
Project description:Distal myopathy with rimmed vacuoles (DMRV), is an autosomal recessive disorder with early adult onset, displays distal dominant muscular involvement and is characterized by the presence of numerous rimmed vacuoles in the affected muscle fibers. The pathophysiology of DMRV has not been clarified yet, although the responsible gene was identified as that encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase involved in the biosynthesis of sialic acids. To identify defective carbohydrate moieties of muscular glycoproteins from DMRV patients, frozen skeletal muscle sections from seven patients with DMRV, as well as normal and pathological controls, were treated with or without sialidase or N-glycosidase F followed by lectin staining and lectin blotting analysis. The sialic acid contents of the O-glycans in the skeletal muscle specimens from the DMRV patients were also measured. We found that Arachis hypogaea agglutinin (PNA) lectin reacted strongly with sarcolemmal glycoproteins in the DMRV patients but not with those in control subjects. alpha-Dystroglycan from the DMRV patients strongly associated with PNA lectin, although that from controls did not. The sialic acid level of the O-glycans in the DMRV muscular glycoproteins with molecular weights of 30 to 200 kd was reduced to 60 to 80% of the control level. The results show that impaired sialyl O-glycan formation in muscular glycoproteins, including alpha-dystroglycan, occurs in DMRV.
| S-EPMC1602383 | biostudies-literature
Project description:Purpose of reviewThe purpose of this review is to summarise the recent developments in trial readiness, natural history studies, and interventional clinical trials for Becker muscular dystrophy (BMD).Recent findingsAs several treatment concepts have claimed to convert patients with Duchenne muscular dystrophy (DMD) into a BMD phenotype, BMD itself has moved into the focus of clinical research. Natural history studies have helped to better characterize patients with BMD and the disease is now a target for interventional trials. In parallel, there have been advances in diagnostics and in the development of preclinical models.SummaryDespite increased collaborative efforts to improve trial readiness amongst patients with BMD, there is still a lack of long-term natural history data, and the broad spectrum of disease severity remains a challenge for well designed clinical trials.
| S-EPMC10487383 | biostudies-literature
Project description:BackgroundDuchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are characterized by muscle wasting leading to loss of ambulation in the first or third decade, respectively. In DMD, the lack of dystrophin hampers connections between intracellular cytoskeleton and cell membrane leading to repeated cycles of necrosis and regeneration associated with inflammation and loss of muscle ordered structure. BMD has a similar muscle phenotype but milder. Here, we address the question whether proteins at variance in BMD compared with DMD contribute to the milder phenotype in BMD, thus identifying a specific signature to be targeted for DMD treatment.MethodsProteins extracted from skeletal muscle from DMD/BMD patients and young healthy subjects were either reduced and solubilized prior two-dimensional difference in gel electrophoresis/mass spectrometry differential analysis or tryptic digested prior label-free liquid chromatography with tandem mass spectrometry. Statistical analyses of proteins and peptides were performed by DeCyder and Perseus software and protein validation and verification by immunoblotting.ResultsProteomic results indicate minor changes in the extracellular matrix (ECM) protein composition in BMD muscles with retention of mechanotransduction signalling, reduced changes in cytoskeletal and contractile proteins. Conversely, in DMD patients, increased levels of several ECM cytoskeletal and contractile proteins were observed whereas some proteins of fast fibres and of Z-disc decreased. Detyrosinated alpha-tubulin was unchanged in BMD and increased in DMD although neuronal nitric oxide synthase was unchanged in BMD and greatly reduced in DMD. Metabolically, the tissue is characterized by a decrement of anaerobic metabolism both in DMD and BMD compared with controls, with increased levels of the glycogen metabolic pathway in BMD. Oxidative metabolism is severely compromised in DMD with impairment of malate shuttle; conversely, it is active in BMD supporting the tricarboxylic acid cycle and respiratory chain. Adipogenesis characterizes DMD, whereas proteins involved in fatty acids beta-oxidation are increased in BMD. Proteins involved in protein/amino acid metabolism, cell development, calcium handling, endoplasmic reticulum/sarcoplasmic reticulum stress response, and inflammation/immune response were increased in DMD. Both disorders are characterized by the impairment of N-linked protein glycosylation in the endoplasmic reticulum. Authophagy was decreased in DMD whereas it was retained in BMD.ConclusionsThe mechanosensing and metabolic disruption are central nodes of DMD/BMD phenotypes. The ECM proteome composition and the metabolic rewiring in BMD lead to preservation of energy levels supporting autophagy and cell renewal, thus promoting the retention of muscle function. Conversely, DMD patients are characterized by extracellular and cytoskeletal protein dysregulation and by metabolic restriction at the level of ?-ketoglutarate leading to shortage of glutamate-derived molecules that over time triggers lipogenesis and lipotoxicity.
| S-EPMC7113522 | biostudies-literature
Project description:BackgroundBecker muscular dystrophy (BMD) is a genetic neuromuscular disease of growing importance caused by in-frame, partial loss-of-function mutations in the dystrophin (DMD) gene. BMD presents with reduced severity compared with Duchenne muscular dystrophy (DMD), the allelic disorder of complete dystrophin deficiency. Significant therapeutic advancements have been made in DMD, including four FDA-approved drugs. BMD, however, is understudied and underserved-there are no drugs and few clinical trials. Discordance in therapeutic efforts is due in part to lack of a BMD mouse model which would enable greater understanding of disease and de-risk potential therapeutics before first-in-human trials. Importantly, a BMD mouse model is becoming increasingly critical as emerging DMD dystrophin restoration therapies aim to convert a DMD genotype into a BMD phenotype.MethodsWe use CRISPR/Cas9 technology to generate bmx (Becker muscular dystrophy, X-linked) mice, which express an in-frame ~40 000 bp deletion of exons 45-47 in the murine Dmd gene, reproducing the most common BMD patient mutation. Here, we characterize muscle pathogenesis using molecular and histological techniques and then test skeletal muscle and cardiac function using muscle function assays and echocardiography.ResultsOverall, bmx mice present with significant muscle weakness and heart dysfunction versus wild-type (WT) mice, despite a substantial improvement in pathology over dystrophin-null mdx52 mice. bmx mice show impaired motor function in grip strength (-39%, P < 0.0001), wire hang (P = 0.0025), and in vivo as well as ex vivo force assays. In aged bmx, echocardiography reveals decreased heart function through reduced fractional shortening (-25%, P = 0.0036). Additionally, muscle-specific serum CK is increased >60-fold (P < 0.0001), indicating increased muscle damage. Histologically, bmx muscles display increased myofibre size variability (minimal Feret's diameter: P = 0.0017) and centrally located nuclei indicating degeneration/regeneration (P < 0.0001). bmx muscles also display dystrophic pathology; however, levels of the following parameters are moderate in comparison with mdx52: inflammatory/necrotic foci (P < 0.0001), collagen deposition (+1.4-fold, P = 0.0217), and sarcolemmal damage measured by intracellular IgM (P = 0.0878). Like BMD patients, bmx muscles show reduced dystrophin protein levels (~20-50% of WT), whereas Dmd transcript levels are unchanged. At the molecular level, bmx muscles express increased levels of inflammatory genes, inflammatory miRNAs and fibrosis genes.ConclusionsThe bmx mouse recapitulates BMD disease phenotypes with histological, molecular and functional deficits. Importantly, it can inform both BMD pathology and DMD dystrophin restoration therapies. This novel model will enable further characterization of BMD disease progression, identification of biomarkers, identification of therapeutic targets and new preclinical drug studies aimed at developing therapies for BMD patients.
| S-EPMC10067474 | biostudies-literature
Project description:Becker muscular dystrophy (BMD) is an X-linked recessive disorder caused by dystrophin gene mutations. The phenotype and evolution of this muscle disorder are extremely clinical variable. In the last years, circulating biomarkers have acquired remarkable importance in their use as noninvasive biological indicators of prognosis and in monitoring muscle disease progression, especially when associated to muscle MRI imaging. We investigated the levels of circulating microRNAs (myo-miRNAs and inflammatory miRNAs) and of the proteins follistatin (FSTN) and myostatin (GDF-8) and compared results with clinical and radiological imaging data. In eight BMD patients, including two cases with evolving lower extremity weakness treated with deflazacort, we evaluated the expression level of 4 myo-miRNAs (miR-1, miR-206, miR-133a, and miR-133b), 3 inflammatory miRNAs (miR-146b, miR-155, and miR-221), FSTN, and GDF-8 proteins. In the two treated cases, there was pronounced posterior thigh and leg fibrofatty replacement assessed by muscle MRI by Mercuri score. The muscle-specific miR-206 was increased in all patients, and inflammatory miR-221 and miR-146b were variably elevated. A significant difference in myostatin expression was observed between steroid-treated and untreated patients. This study suggests that microRNAs and myostatin protein levels could be used to better understand the progression and management of the disease.
| S-EPMC7554733 | biostudies-literature
Project description:To improve assessment of dystrophinopathy, the aim of this study was to identify whether serum creatinine (Crn) level reflects disease severity.Biochemical, Vignos score, and genetic data were collected on 212 boys with dystrophinopathy.Serum Crn level had a strong inverse correlation with Vignos score by simple correlation (r = -0.793) and partial correlation analysis after adjustment for age, height, and weight (r = -0.791; both P < 0.01). Serum Crn level was significantly higher in patients with in-frame than out-of-frame mutations (Z = -4.716, ?P < 0.01) and in Becker muscular dystrophy (BMD) patients than Duchenne muscular dystrophy (DMD) patients at ages 4, 5, 7, and 9?yr (all P < 0.0125). After adjusting for age, height, and weight, BMD patients still had a significantly higher serum Crn level than DMD patients (? = 7.140, ?t = 6.277, ?P < 0.01).Serum Crn level reflected disease severity and may serve as a supplemental index to distinguish DMD from BMD in clinical practice.
| S-EPMC4380093 | biostudies-literature
Project description:Follistatin is a ubiquitous secretory propeptide that functions as a potent inhibitor of the myostatin pathway, resulting in an increase in skeletal muscle mass. Its ability to interact with the pituitary activin-inhibin axis and suppress the secretion of follicle-stimulating hormone (FSH) called for caution in its clinical applicability. This limitation was circumvented by the use of one of the alternatively spliced follistatin variants, FS344, undergoing post-translational modification to FS315. This follistatin isoform is serum-based, and has a 10-fold lower affinity to activin compared to FS288. Preclinical studies of intramuscular delivery of the follistatin gene demonstrated safety and efficacy in enhancing muscle mass. We herein review the evidence supporting the utility of follistatin as a genetic enhancer to improve cellular performance. In addition, we shed light on the results of the first clinical gene transfer trial using the FS344 isoform of follistatin in subjects with Becker muscular dystrophy as well as the future directions for clinical gene therapy trials using follistatin.
| S-EPMC5240576 | biostudies-literature
Project description:Background and aim Becker muscular dystrophy (BMD) is an X-linked disease caused by an in-frame mutation in the dystrophin gene, which is considered an allelic disorder to the most severe form of dystrophinopahies, Duchenne muscular dystrophy, which leads to skeletal and cardiac muscle involvement and results in dilated cardiomyopathy (DCM). The aim of this study is to present our ECG data and the significance of this data in the early detection of DCM in these patients. Methods This is a retrospective study. All patients known to the clinical Genetic Clinic and Queen Alia Heart Center in Jordan with a diagnosis of Becker muscular dystrophy from the year 2011-2022 are offered cardiac evaluation according to the guidelines, which included clinical assessment, electrocardiograph, and 2-D echocardiograph (echo) at the time of diagnosis and every five years thereafter once the initial assessment was normal. All the records were retrieved and analyzed. Results Fifty-three patients of all ages with genetically confirmed BMD were identified. Twelve had no record as they didn't attend any cardiac evaluation. Forty-one were under regular clinical follow-up. Two were excluded as they died, and another four had no recorded data in our center. Ultimately, 35 patients were included and studied. The mean age was 30.5 years ± 22.1, ranging from two to seventy-seven years of age. Twenty-seven (77%) had abnormal ECG. High voltage R wave in V2 and V1 was the most common finding, followed by repolarisation abnormalities and Q wave (43%, 17%, 13%, and 11% respectively). Incomplete right bundle branch block in 4% as well as R/S ratio >1.2. U wave abnormalities in 3% and sinus tachycardia were found in only one patient. Conclusion Cardiac surveillance for patients with Becker muscular dystrophy is mandatory after the age of 16. Q wave and repolarisation changes should be taken seriously as early signs of dilated cardiomyopathy, even if the echo is normal.
| S-EPMC10665640 | biostudies-literature
Project description:BackgroundThe goal of this study is to identify the hub genes for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) via weighted correlation network analysis (WGCNA).MethodsThe gene expression profile of vastus lateralis biopsy samples obtained in 17 patients with DMD, 11 patients with BMD and 6 healthy individuals was downloaded from the Gene Expression Omnibus (GEO) database (GSE109178). After obtaining different expressed genes (DEGs) via GEO2R, WGCNA was conducted using R package, modules and genes that highly associated with DMD, BMD, and their age or pathology were screened. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis and protein-protein interaction (PPI) network analysis were also conducted. Hub genes and highly correlated clustered genes were identified using Search Tool for the Retrieval of Interacting Genes (STRING) and Cystoscape software.ResultsOne thousand four hundred seventy DEGs were identified between DMD and control, with 1281 upregulated and 189 downregulated DEGs. Four hundred and twenty DEGs were found between BMD and control, with 157 upregulated and 263 upregulated DEGs. Fourteen modules with different colors were identified for DMD vs control, and 7 modules with different colors were identified for BMD vs control. Ten hub genes were summarized for DMD and BMD respectively, 5 hub genes were summarized for BMD age, 5 and 3 highly correlated clustered genes were summarized for DMD age and BMD pathology, respectively. In addition, 20 GO enrichments were found to be involved in DMD, 3 GO enrichments were found to be involved in BMD, 3 GO enrichments were found to be involved in BMD age.ConclusionIn DMD, several hub genes were identified: C3AR1, TLR7, IRF8, FYB and CD33(immune and inflammation associated genes), TYROBP, PLEK, AIF1(actin reorganization associated genes), LAPTM5 and NT5E(cell death and arterial calcification associated genes, respectively). In BMD, a number of hub genes were identified: LOX, ELN, PLEK, IKZF1, CTSK, THBS2, ADAMTS2, COL5A1(extracellular matrix associated genes), BCL2L1 and CDK2(cell cycle associated genes).
| S-EPMC8684282 | biostudies-literature