scholarly journals 34. Phi C31 Integrase System Enhances Dystrophin Gene Expression in Skeletal Muscle of Mouse Models for Duchenne Muscular Dystrophy

2006 ◽  
Vol 13 ◽  
pp. S14-S15
Author(s):  
Carmen Bertoni ◽  
Sohail Jarrahian ◽  
Thurman M. Wheeler ◽  
Yining Li ◽  
Eric C. Olivares ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Dystrophin Gene

scholarly journals Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

2019 ◽  
Vol 8 ◽  
pp. 204800401987958
Author(s):  
HR Spaulding ◽  
C Ballmann ◽  
JC Quindry ◽  
MB Hudson ◽  
JT Selsby
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Disease Progression ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Dystrophin Deficiency ◽  
Muscle Wasting Disease ◽  
Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

scholarly journals Duchenne muscular dystrophy patients lacking the dystrophin isoforms Dp140 and Dp71 and mouse models lacking Dp140 have a more severe motor phenotype

2021 ◽  
Author(s):  
Mary Chesshyre ◽  
Deborah Ridout ◽  
Yasumasa Hashimoto ◽  
Yoko Ookubo ◽  
Silvia Torelli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Grip Strength ◽  
Mouse Models ◽  
Motor Function ◽  
Wild Type ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Background Duchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this. Methods Functional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice. Results In DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (p<0.01) and 4.9 points lower in group 3 than group 2 (p=0.05). Mean peak NSAA scores were 4.0 points lower in group 3 than group 1 (p<0.01), 2.4 points lower in group 3 than group 2 (p=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04). Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01). Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures. Conclusions DMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.

scholarly journals Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle

2002 ◽  
Vol 99 (23) ◽  
pp. 15000-15005 ◽  
Author(s):  
J. N. Haslett ◽  
D. Sanoudou ◽  
A. T. Kho ◽  
R. R. Bennett ◽  
S. A. Greenberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy

Abstract 44: Telomere and Mitochondrial Dysfunction in Duchenne Muscular Dystrophy

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alex C Chang ◽  
Sang-Ging Ong ◽  
Joseph Wu ◽  
Helen M Blau
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Dilated Cardiomyopathy ◽  
Mitochondrial Dysfunction ◽  
Telomere Length ◽  
Dystrophin Gene ◽  
Glycoprotein Complex ◽  
The Difference

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disease that is result of mutations in the dystrophin gene and is the most common myopathic disease in humans with a prevalence of one in every 3500 males. Dystrophin is crucial for the formation of a dystrophin-glycoprotein complex (DGC), which connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix in both skeletal and cardiac muscles. In the heart, loss of dystrophin leads to increased fibrosis and death in the third decade of life due to dilated cardiomyopathy. A conundrum in studying and developing therapies for DMD has been the lack of a mouse model that fully recapitulates the clinical phenotype, as mice that lack dystrophin (mdx model), unlike patients, exhibit only mild skeletal muscle defects, essentially no cardiac defects and have a relatively normal lifespan. Our lab reasoned that the difference in the manifestation of the disease in mice and humans could be telomere length, as mice have substantially longer telomeres than humans. We created a novel mouse model with shortened telomere lengths (similar to humans) that fully recapitulates the skeletal muscle (Cell. 2010;143:1059-1071; the mdx/mTRKO model) and cardiac muscle phenotype of DMD (Nat Cell Biol. 2013; 15:895-904; dilated cardiomyopathy). Interestingly, we observed a relative 45% reduction in cardiomyocyte telomere length in our mdx/mTRKO animals (3 animals per group, N = 300-400) as well as patient samples (4 DMD patient samples, N = 40-95). Here we present new evidence of mitochondrial dysfunction and telomere dysfunction.

Gene expression profiling of Duchenne muscular dystrophy skeletal muscle

Neurogenetics ◽  
2003 ◽  
Vol 4 (4) ◽  
pp. 163-171 ◽  
Author(s):  
Judith N. Haslett ◽  
Despina Sanoudou ◽  
Alvin T. Kho ◽  
Mei Han ◽  
Richard R. Bennett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Expression Profiling ◽  
Expression Profiling

scholarly journals Galectin-3 and N-acetylglucosamine promote myogenesis and improve skeletal muscle function in the mdx model of Duchenne muscular dystrophy

2017 ◽  
Author(s):  
Ann Rancourt ◽  
Sébastien Dufresne ◽  
Guillaume St-Pierre ◽  
Julie-Christine Lévesque ◽  
Haruka Nakamura ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Basal Lamina ◽  
Dystrophin Gene ◽  
Muscle Membrane ◽  
Skeletal Muscle Function ◽  
Myogenic Stem Cells ◽  
Galectin 3

AbstractThe muscle membrane, sarcolemma, must be firmly attached to the basal lamina. The failure of proper attachment results in muscle injury, which is the underlying cause of Duchenne muscular dystrophy (DMD), where mutations in the dystrophin gene disrupts the firm adhesion. In DMD patients, even moderate contraction causes damage, leading to progressive muscle degeneration. The damaged muscles are repaired through myogenesis. Consequently, myogenesis is highly active in DMD patients, and the repeated activation of myogenesis leads to the exhaustion of the myogenic stem cells. Therefore, approaches to reducing the risk of the exhaustion are to develop a treatment that strengthens the interaction between the sarcolemma and the basal lamina, and increases the efficiency of myogenesis. Galectin-3 is an oligosaccharide-binding protein and known to be involved in cell-cell interactions and cell-matrix interactions. Galectin-3 is expressed in myoblasts and skeletal muscle while its function in muscle remains elusive. In this study, we found evidence that galectin-3 and the monosaccharide N-acetylglucosamine, which increases the ligands (oligosaccharides) of galectin-3, promotes myogenesis in vitro. Moreover, in the mdx mouse model of DMD, treatment with N-acetylglucosamine increased the muscle force production. Our results demonstrate that treatment with N-acetylglucosamine can mitigate the burden of DMD.

scholarly journals Circadian Genes as Exploratory Biomarkers in DMD: Results From Both the mdx Mouse Model and Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Rachele Rossi ◽  
Maria Sofia Falzarano ◽  
Hana Osman ◽  
Annarita Armaroli ◽  
Chiara Scotton ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Circadian Rhythm ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Expression Profiles ◽  
Gene Mutations ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Muscle Biopsies

Duchenne muscular dystrophy (DMD) is a rare genetic disease due to dystrophin gene mutations which cause progressive weakness and muscle wasting. Circadian rhythm coordinates biological processes with the 24-h cycle and it plays a key role in maintaining muscle functions, both in animal models and in humans. We explored expression profiles of circadian circuit master genes both in Duchenne muscular dystrophy skeletal muscle and in its animal model, the mdx mouse. We designed a customized, mouse-specific Fluidic-Card-TaqMan-based assay (Fluid-CIRC) containing thirty-two genes related to circadian rhythm and muscle regeneration and analyzed gastrocnemius and tibialis anterior muscles from both unexercised and exercised mdx mice. Based on this first analysis, we prioritized the 7 most deregulated genes in mdx mice and tested their expression in skeletal muscle biopsies from 10 Duchenne patients. We found that CSNK1E, SIRT1, and MYOG are upregulated in DMD patient biopsies, consistent with the mdx data. We also demonstrated that their proteins are detectable and measurable in the DMD patients’ plasma. We suggest that CSNK1E, SIRT1, and MYOG might represent exploratory circadian biomarkers in DMD.

scholarly journals Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yacine Kharraz ◽  
Joana Guerra ◽  
Patrizia Pessina ◽  
Antonio L. Serrano ◽  
Pura Muñoz-Cánoves
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Inflammatory Cells ◽  
Dystrophin Gene ◽  
New Developments ◽  
Muscle Stem Cells ◽  
Muscle Fibrosis ◽  
Tissue Healing ◽  
And Function

Fibrosis is the aberrant deposition of extracellular matrix (ECM) components during tissue healing leading to loss of its architecture and function. Fibrotic diseases are often associated with chronic pathologies and occur in a large variety of vital organs and tissues, including skeletal muscle. In human muscle, fibrosis is most readily associated with the severe muscle wasting disorder Duchenne muscular dystrophy (DMD), caused by loss of dystrophin gene function. In DMD, skeletal muscle degenerates and is infiltrated by inflammatory cells and the functions of the muscle stem cells (satellite cells) become impeded and fibrogenic cells hyperproliferate and are overactivated, leading to the substitution of skeletal muscle with nonfunctional fibrotic tissue. Here, we review new developments in our understanding of the mechanisms leading to fibrosis in DMD and several recent advances towards reverting it, as potential treatments to attenuate disease progression.

scholarly journals Gene expression effects of glucocorticoid and mineralocorticoid receptor agonists and antagonists on normal human skeletal muscle

2017 ◽  
Vol 49 (6) ◽  
pp. 277-286 ◽  
Author(s):  
Jessica A. Chadwick ◽  
J. Spencer Hauck ◽  
Celso E. Gomez-Sanchez ◽  
Elise P. Gomez-Sanchez ◽  
Jill A. Rafael-Fortney
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Skeletal Muscles ◽  
Human Skeletal Muscle ◽  
Expression Profiles ◽  
Combined Treatment ◽  
Gene Expression Profiles ◽  
Steroid Hormone Receptors

Mineralocorticoid and glucocorticoid receptors are closely related steroid hormone receptors that regulate gene expression through many of the same hormone response elements. However, their transcriptional activities and effects in skeletal muscles are largely unknown. We recently identified mineralocorticoid receptors (MR) in skeletal muscles after finding that combined treatment with the angiotensin-converting enzyme inhibitor lisinopril and MR antagonist spironolactone was therapeutic in Duchenne muscular dystrophy mouse models. The glucocorticoid receptor (GR) agonist prednisolone is the current standard-of-care treatment for Duchenne muscular dystrophy because it prolongs ambulation, likely due to its anti-inflammatory effects. However, data on whether glucocorticoids have a beneficial or detrimental direct effect on skeletal muscle are controversial. Here, we begin to define the gene expression profiles in normal differentiated human skeletal muscle myotubes treated with MR and GR agonists and antagonists. The MR agonist aldosterone and GR agonist prednisolone had highly overlapping gene expression profiles, supporting the notion that prednisolone acts as both a GR and MR agonist that may have detrimental effects on skeletal muscles. Co-incubations with aldosterone plus either nonspecific or selective MR antagonists, spironolactone or eplerenone, resulted in similar numbers of gene expression changes, suggesting that both drugs can block MR activation to a similar extent. Eplerenone treatment alone decreased a number of important muscle-specific genes. This information may be used to develop biomarkers to monitor clinical efficacy of MR antagonists or GR agonists in muscular dystrophy, develop a temporally coordinated treatment with both drugs, or identify novel therapeutics with more specific downstream targets.

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