scholarly journals Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 706
Author(s):  
Jacopo Morroni ◽  
Leonardo Schirone ◽  
Daniele Vecchio ◽  
Carmine Nicoletti ◽  
Luca D’Ambrosio ◽  
...  
Keyword(s):  
Large Scale ◽  
Late Onset ◽  
Heart Function ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Old Patients ◽  
Cardiac Pathology ◽  
Human Pathology ◽  
Heart Pathology ◽  
Novel Therapeutic Strategies

Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD). Around 90% of 18-year-old patients already show signs of DMD-related cardiomyopathy, and cardiac failure is rising as the main cause of death among DMD patients. The evaluation of novel therapies for the treatment of dystrophic heart problems depends on the availability of animal models that closely mirror the human pathology. The widely used DMD animal model, the mdx mouse, presents a milder cardiac pathology compared to humans, with a late onset, which precludes large-scale and reliable studies. In this study, we used an exercise protocol to accelerate and worsen the cardiac pathology in mdx mice. The mice were subjected to a 1 h-long running session on a treadmill, at moderate speed, twice a week for 8 weeks. We demonstrate that subjecting young mdx mice (4-week-old) to “endurance” exercise accelerates heart pathology progression, as shown by early fibrosis deposition, increases necrosis and inflammation, and reduces heart function compared to controls. We believe that our exercised mdx model represents an easily reproducible and useful tool to study the molecular and cellular networks involved in dystrophic heart alterations, as well as to evaluate novel therapeutic strategies aimed at ameliorating dystrophic heart pathology.

scholarly journals Profiling of Age-Related Changes in theTibialis AnteriorMuscle Proteome of the mdx Mouse Model of Dystrophinopathy

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Steven Carberry ◽  
Margit Zweyer ◽  
Dieter Swandulla ◽  
Kay Ohlendieck
Keyword(s):  
Muscular Dystrophy ◽  
Tibialis Anterior ◽  
Large Scale ◽  
Small Heat Shock Protein ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Global Changes ◽  
Altered Expression ◽  
Age Related

X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdxtibialis anteriormuscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdxtibialis anteriormuscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy.

SERCA-mediated calcium uptake in the DBA/2J vs C57BL/10 mdx models of Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Riley EG Cleverdon ◽  
Kennedy C Whitley ◽  
Daniel M Marko ◽  
Sophie I Hamstra ◽  
Jessica L Braun ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Duchenne Muscular Dystrophy ◽  
Sarcoplasmic Reticulum ◽  
Muscular Dystrophy ◽  
Calcium Uptake ◽  
Late Onset ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Mild Phenotype ◽  
Serca Pump

The C57BL/10ScSn-Dmdmdx/J (C57 mdx) mouse is the most commonly used murine model of Duchenne muscular dystrophy (DMD) but displays a mild phenotype with a late onset, greatly limiting translatability to clinical research. In consequence, the D2.B10-Dmdmdx/J (D2 mdx) mouse was created and produces a more severe, early onset phenotype. Mechanistic insights of the D2 mdx phenotype have yet to be elucidated, specifically related to sarcoplasmic reticulum (SR) calcium (Ca2+) handling. In our study, we aimed to determine if SR Ca2+ handling differences in the D2 mdx versus the C57 mdx mouse could explain model phenotypes. Firstly, analyses determined that D2 mdx mice ambulate less and have weaker muscles, but have greater energy expenditure than C57 counterparts. SR Ca2+ handling measures determined that only D2 mdx mice have impaired SR calcium intake in the gastrocnemius, left ventricle and diaphragm. This was coupled with decrements in maximal sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity and greater activation of the Ca2+-activated protease, calpain, in the gastrocnemius. Overall, our study is the first to determine that SR Ca2+ handling is impaired in the D2 mdx mouse, specifically at the level of the SERCA pump. 

Fine structure of early degenerating myofibers in the tibialis anterior of young ‘MDX’ mouse

1988 ◽  
Vol 46 ◽  
pp. 322-323
Author(s):  
H.D. Geissinger ◽  
C.K. McDonald-Taylor
Keyword(s):  
Fine Structure ◽  
Muscle Regeneration ◽  
Tibialis Anterior ◽  
Genetic Defect ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Histopathological Changes ◽  
Electron Microscopic ◽  
Dystrophic Mouse ◽  
Preliminary Study

A new strain of mice, which had arisen by mutation from a dystrophic mouse colony was designated ‘mdx’, because the genetic defect, which manifests itself in brief periods of muscle destruction followed by episodes of muscle regeneration appears to be X-linked. Further studies of histopathological changes in muscle from ‘mdx’ mice at the light microscopic or electron microscopic levels have been published, but only one preliminary study has been on the tibialis anterior (TA) of ‘mdx’ mice less than four weeks old. Lesions in the ‘mdx’ mice vary between different muscles, and centronucleation of fibers in all muscles studied so far appears to be especially prominent in older mice. Lesions in young ‘mdx’ mice have not been studied extensively, and the results appear to be at variance with one another. The degenerative and regenerative aspects of the lesions in the TA of 23 to 26-day-old ‘mdx’ mice appear to vary quantitatively.

Association between ALDH2 Gene Polymorphism and Late-onset Alzheimer Disease: An Up-to-date Meta-analysis

2020 ◽  
Vol 17 (2) ◽  
pp. 105-111
Author(s):  
Haitao Liu ◽  
Wei Ge ◽  
Wei Chen ◽  
Xue Kong ◽  
Weiming Jian ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Large Scale ◽  
Late Onset ◽  
Meta Analysis ◽  
Case Control ◽  
Cochrane Library ◽  
Positive Trend ◽  
Case Control Studies ◽  
China National Knowledge Infrastructure ◽  
Aldh2 Gene

Objectives: Previous case-control studies have focused on the relationship between ALDH2 gene polymorphism and late-onset Alzheimer's Disease (LOAD), but no definite unified conclusion has been reached. Therefore, the correlation between ALDH2 Glu504Lys polymorphism and LOAD remains controversial. To analyze the correlation between ALDH2 polymorphism and the risk of LOAD, we implemented this up-to-date meta-analysis to assess the probable association. Methods: Studies were searched through China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals, China Biology Medicine, PubMed, Cochrane Library, Clinical- Trials.gov, Embase, and MEDLINE from January 1, 1994 to December 31, 2018, without any restrictions on language and ethnicity. Results: Five studies of 1057 LOAD patients and 1136 healthy controls met our criteria for the analysis. Statistically, the ALDH2 GA/AA genotype was not linked with raising LOAD risk (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 0.96-2.28, p = 0.07). In subgroup analysis, the phenomenon that men with ALDH2*2 had higher risk for LOAD (OR = 1.72, 95%CI = 1.10-2.67, p = 0.02) was observed. Conclusions: This study comprehends only five existing case-control studies and the result is negative. The positive trend might appear when the sample size is enlarged. In the future, more large-scale casecontrol or cohort studies should be done to enhance the association between ALDH2 polymorphism and AD or other neurodegenerative diseases.

Global/temporal gene expression in diaphragm and hindlimb muscles of dystrophin-deficient (mdx) mice

2002 ◽  
Vol 283 (3) ◽  
pp. C773-C784 ◽  
Author(s):  
Karl Rouger ◽  
Martine Le Cunff ◽  
Marja Steenman ◽  
Marie-Claude Potier ◽  
Nathalie Gibelin ◽  
...  
Keyword(s):  
Dystrophin Gene ◽  
Diaphragm Muscle ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
First Year ◽  
Temporal Gene Expression ◽  
Cell Functions ◽  
Hindlimb Muscles ◽  
Genes Encoding ◽  
Dystrophin Protein

The mdx mouse is a model for human Duchenne muscular dystrophy (DMD), an X-linked degenerative disease of skeletal muscle tissue characterized by the absence of the dystrophin protein. The mdx mice display a much milder phenotype than DMD patients. After the first week of life when all mdx muscles evolve like muscles of young DMD patients, mdx hindlimb muscles substantially compensate for the lack of dystrophin, whereas mdx diaphragm muscle becomes progressively affected by the disease. We used cDNA microarrays to compare the expression profile of 1,082 genes, previously selected by a subtractive method, in control and mdx hindlimb and diaphragm muscles at 12 time points over the first year of the mouse life. We determined that 1) the dystrophin gene defect induced marked expression remodeling of 112 genes encoding proteins implicated in diverse muscle cell functions and 2) two-thirds of the observed transcriptomal anomalies differed between adult mdx hindlimb and diaphragm muscles. Our results showed that neither mdx diaphram muscle nor mdx hindlimb muscles evolve entirely like the human DMD muscles. This finding should be taken under consideration for the interpretation of future experiments using mdx mice as a model for therapeutic assays.

scholarly journals High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer

2021 ◽  
Author(s):  
Jeong Eun Kim ◽  
Jaeyong Choi ◽  
Chang-Ohk Sung ◽  
Yong Sang Hong ◽  
Sun Young Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Large Scale ◽  
Late Onset ◽  
Age Groups ◽  
The Cancer Genome Atlas ◽  
Whole Genome ◽  
Genome Doubling ◽  
Whole Genome Doubling ◽  
Early Onset Colorectal Cancer

AbstractThe global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.

Inspiratory loading does not accelerate dystrophy inmdx mouse diaphragm: implications for regenerative therapy

2003 ◽  
Vol 94 (2) ◽  
pp. 411-419 ◽  
Author(s):  
Alexander S. Krupnick ◽  
Jianliang Zhu ◽  
Taitan Nguyen ◽  
Daniel Kreisel ◽  
Keki R. Balsara ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Blue Dye ◽  
Regenerative Therapy ◽  
Regenerative Capacity ◽  
Progressive Degeneration ◽  
Mouse Diaphragm ◽  
The Relationship

Since the finding that the mdx mouse diaphragm, in contrast to limb muscles, undergoes progressive degeneration analogous to that seen in Duchenne muscular dystrophy, the relationship between the workload on a muscle and the pathogenesis of dystrophy has remained controversial. We increased the work performed by the mdx mouse diaphragm in vivo by tracheal banding and evaluated the progression of dystrophic changes in that muscle. Despite the establishment of dramatically increased respiratory workload and accelerated myofiber damage documented by Evans blue dye, no change in the pace of progression of dystrophy was seen in banded animals vs. unbanded, sham-operated controls. At the completion of the study, more centrally nucleated fibers were evident in the diaphragms of banded mdx mice than in sham-operated mdx controls, indicating that myofiber regeneration increases to meet the demands of the work-induced damage. These data suggest that there is untapped regenerative capacity in dystrophin-deficient muscle and validates experimental efforts aimed at augmenting regeneration within skeletal muscle as a therapeutic strategy in the treatment of dystrophinopathies.

Abstract 17081: End Stage Mitochondrial Cardiomyopathy And Heart Transplantation Due To Pathogenic Biallelic C1QBP Variants

Circulation ◽  
2021 ◽  
Vol 144 (Suppl_2) ◽  
Author(s):  
Nicholas S Wilcox ◽  
Stuart Prenner ◽  
Marisa Cevasco ◽  
Courtney Condit ◽  
Amy Goldstein ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Heart Transplantation ◽  
Genome Sequencing ◽  
Large Scale ◽  
De Novo ◽  
Late Onset ◽  
Genetic Disorder ◽  
Disease Onset ◽  
Serum Lactate ◽  
Metabolic Decompensation

Case Presentation: A 29-year-old male with LVH diagnosed in childhood was admitted with acute HF. TTE showed LVEF 5-10% and LV thrombi for which he was anticoagulated. He received inappropriate ICD shocks due to T wave oversensing, leading to cardiogenic shock requiring VA-ECMO support. Serum lactate peaked at 17 mmol/L due to cardiac and metabolic decompensation. He underwent heart transplantation (HT) on hospital day (HD) 8 and tolerated standard immunosuppression. First endomyocardial biopsy showed acute cellular rejection requiring pulse steroids. He was discharged on HD 33. Trio whole exome and mitochondrial genome sequencing revealed biallelic variants in complement component 1Q subcomponent-binding protein ( C1QBP ), due to a maternally inherited likely pathogenic variant c.612C>G (p.F204L in exon 5) and an apparently de novo deletion of 17p13.2, spanning exons 4-6 of C1QBP and exon 6 of the RPAIN gene. Mitochondrial genome sequencing of the explanted heart revealed multiple large-scale mitochondrial DNA deletions at 33% heteroplasmy. Discussion: C1QBP variants are associated with mitochondrial and multi-organ dysfunction. Only 12 patients exhibiting biallelic C1QBP variants are reported. Four died in the peripartum period due to fetal hydrops or HF; 5 exhibited early-onset cardiomyopathy (CM); 3 others had late-onset ophthalmoplegia without CM. The p.F204L variant has been reported in 1 patient with compound C1QBP p.F204L/p.C186S heterozygosity who died from hydrops fetalis and a second with p.F204L homozygosity with late-onset ophthalmoplegia and skeletal myopathy without CM. Differences in the size, heteroplasmy, and tissue distribution of mitochondrial genome secondary deletions may explain variability in disease onset and progression. We present the first patient with biallelic pathogenic C1QBP gene variants with mitochondrial CM to undergo HT and highlight the diagnosis and management of an exceptionally uncommon genetic disorder.

Muscle genome-wide expression profiling during disease evolution in mdx mice

2009 ◽  
Vol 37 (2) ◽  
pp. 119-132 ◽  
Author(s):  
Mario Marotta ◽  
Claudia Ruiz-Roig ◽  
Yaris Sarria ◽  
Jose Luis Peiro ◽  
Fatima Nuñez ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Genetic Defect ◽  
Strong Relationship ◽  
Pcr Analysis ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Matrix Remodeling ◽  
Disease Evolution ◽  
Genome Wide ◽  
Muscle Necrosis

Mdx mice show a milder phenotype than Duchenne patients despite bearing an analogous genetic defect. Our aim was to sort out genes, differentially expressed during the evolution of skeletal muscle mdx mouse disease, to elucidate the mechanisms by which these animals overcome the lack of dystrophin. Genome-wide microarray-based gene expression analysis was carried out at 3 wk and 1.5 and 3 mo of life. Candidate genes were selected by comparing: 1) mdx vs. controls at each point in time, and 2) mdx mice and 3) control mice among the three points in time. The first analysis showed a strong upregulation (96%) of inflammation-related genes and in >75% of genes related to cell adhesion, muscle structure/regeneration, and extracellular matrix remodeling during mdx disease evolution. Lgals3, Postn, Ctss, and Sln genes showed the strongest variations. The analysis performed among points in time demonstrated significant changes in Ecm1, Spon1, Thbs1, Csrp3, Myo10, Pde4b, and Adamts-5 exclusively during mdx mice lifespan. RT-PCR analysis of Postn, Sln, Ctss, Thbs1, Ecm1, and Adamts-5 expression from 3 wk to 9 mo, confirmed microarray data and demonstrated variations beyond 3 mo of age. A high-confidence functional network analysis demonstrated a strong relationship between them and showed two main subnetworks, having Dmd- Utrn- Myo10 and Adamts5- Thbs1- Spon1-Postn as principal nodes, which are functionally linked to Abca1, Actn4, Crebbp, Csrp3, Lama1, Lama3, Mical2, Mical3, Myf6, Pxn, and Sparc genes. Candidate genes may participate in the decline of muscle necrosis in mdx mice and could be considered potential therapeutic targets for Duchenne patients.

scholarly journals Ataxias with Autosomal, X-Chromosomal or Maternal Inheritance

2009 ◽  
Vol 36 (4) ◽  
pp. 409-428 ◽  
Author(s):  
Josef Finsterer
Keyword(s):  
Ataxia Telangiectasia ◽  
Large Scale ◽  
Autosomal Recessive ◽  
Autosomal Dominant ◽  
Late Onset ◽  
Fragile X ◽  
Axonal Neuropathy ◽  
Friedreich Ataxia ◽  
Point Mutations ◽  
Spinocerebellar Ataxias

Heredoataxias are a group of genetic disorders with a cerebellar syndrome as the leading clinical manifestation. The current classification distinguishes heredoataxias according to the trait of inheritance into autosomal dominant, autosomal recessive, X-linked, and maternally inherited heredoataxias. The autosomal dominant heredoataxias are separated into spinocerebellar ataxias (SCA1-8, 10-15, 17-23, 25-30, and dentato-rubro-pallido-luysian atrophy), episodic ataxias (EA1-7), and autosomal dominant mitochondrial heredoataxias (Leigh syndrome, MIRAS, ADOAD, and AD-CPEO). The autosomal recessive ataxias are separated into Friedreich ataxia, ataxia due to vitamin E deficiency, ataxia due to Abeta-lipoproteinemia, Refsum disease, late-onset Tay-Sachs disease, cerebrotendineous xanthomatosis, spinocerebellar ataxia with axonal neuropathy, ataxia telangiectasia, ataxia telangiectasia-like disorder, ataxia with oculomotor apraxia 1 and 2, spastic ataxia of Charlevoix-Saguenay, Cayman ataxia, Marinesco-Sjögren syndrome, and autosomal recessive mitochondrial ataxias (AR-CPEO, SANDO, SCAE, AHS, IOSCA, MEMSA, LBSL CoQ-deficiency, PDC-deficiency). Only two of the heredoataxias, fragile X/tremor/ataxia syndrome, and XLSA/A are transmitted via an X-linked trait. Maternally inherited heredoataxias are due to point mutations in genes encoding for tRNAs, rRNAs, respiratory chain subunits or single large scale deletions/duplications of the mitochondrial DNA and include MELAS, MERRF, KSS, PS, MILS, NARP, and non-syndromic mitochondrial disorders. Treatment of heredoataxias is symptomatic and supportive and may have a beneficial effect in single patients.**Please see page 424 for abbreviation list.

Sign in / Sign up

Export Citation Format

Share Document