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 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 Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 837 ◽  
Author(s):  
Chengmei Sun ◽  
Luoan Shen ◽  
Zheng Zhang ◽  
Xin Xie
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuromuscular Disorders ◽  
Dystrophin Gene ◽  
Current Status ◽  
Muscle Stem Cells ◽  
Cell Based Therapy ◽  
Dystrophin Protein

Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.

Reparative dysfunction during muscle regeneration in Duchenne muscular dystrophy: therapeutic approaches to modulating the muscle environment and muscle stem cells

2019 ◽  
Author(s):  
◽  
Michael Everette Nance
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Regeneration ◽  
Genetic Mutation ◽  
Critical Determinant ◽  
Muscle Stem Cells ◽  
Dystrophin Protein

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT REQUEST OF AUTHOR.] Duchenne muscular dystrophy (DMD) is a lethal muscular dystrophy resulting from functional loss of the dystrophin protein, a critical sub-sarcolemmal protein involved in membrane stability. While reparative dysfunction is thought to be a critical determinant of disease progression in humans, regeneration is not significantly impaired in the murine muscular dystrophy (mdx) model. Furthermore, it is not well understood if reparative dysfunction is related to inherent defects in stem cells or chronic alterations in the muscle environment due to disease related remodeling. To address these observed discrepancies, we adapted a whole muscle transplant model to study the in vivo regeneration of intact pieces of skeletal muscle from normal and dystrophic dogs (cDMD), a physiological and clinically relevant model to humans. Regeneration in cDMD muscle grafts was significantly attenuated compared to normal and predisposed to the development of skeletal muscle tumors. We used an adeno-associated virus (AAV) expressing a micro-dystrophin protein to specifically rescue the muscle environment by preventing fiber damage while retaining dystrophin-null SCs. AAV.micro-dystrophin rescued the environment by improving fibrosis, stiffness, and fiber orientation, which significantly improved early muscle regeneration but not late regeneration (2 greater than and less than 4 months post-transplant) via enhancing muscle stem cells differentiation. We next developed Cre- and CRISPR-cas9 gene editing strategies to test the ability of AAV serotype 9 to transduce and treat the genetic mutation in muscle stem cells. We observed efficient SC transduction when used as a single vector expressing Cre. Dual-vector CRISPR-cas9 SC transduction was inefficient and likely related to the requirement for two vectors, promoter usage, and mechanistic differences between Cre-recombination and CRISPR genome editing.

scholarly journals Chloroquine Decreases Cardiomyocyte Autophagy and Improves Cardiac Function in a Mouse Model of Duchenne Muscular Dystrophy

2021 ◽  
Author(s):  
Takaya Hirata ◽  
Shiro Baba ◽  
Kentaro Akagi ◽  
Daisuke Yoshinaga ◽  
Katsutsugu Umeda ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Therapeutic Modality ◽  
Cardiomyocyte Autophagy ◽  
And Function ◽  
Ventricle Size

Abstract Background: Duchenne muscular dystrophy (DMD), a severe degenerative skeletal and cardiac muscle disease, has a poor prognosis, and no curative treatments are available. Because autophagy has been reported to contribute to skeletal muscle degeneration, therapies targeting autophagy are expected to improve skeletal muscle hypofunction. However, the role of this regulatory mechanism has not been evaluated clearly in DMD cardiomyocytes. Methods: In the present study, we demonstrated that autophagy was enhanced in the cardiomyocytes of mdx mice, a model of DMD, and that increased autophagy contributed to the development of cardiomyopathy in this context. Results: As assessed by GFP-mRFP-LC3 transfection, autophagosomes were more abundant in cardiomyocytes of mdx mice compared with control wild-type (WT) mice. The number of autophagosomes was significantly enhanced by isoproterenol-induced cardiac stress (4 weeks) in cardiomyocytes of mdx but not WT mice. Simultaneously, isoproterenol increased cardiomyocyte fibrosis in mdx but not WT mice. Administration of chloroquine, an autophagy inhibitor, significantly decreased cardiomyocyte autophagy and fibrosis in mdx mice, even after isoproterenol treatment. Left ventricle size and function were evaluated by echocardiography. Left ventricular contraction was decreased in mdx mice after isoproterenol treatment compared with control mice, which was alleviated by chloroquine administration.Conclusions: These findings suggested that heart failure of DMD could be associated with autophagy. Therefore, autophagy inhibitors, such as chloroquine, are a potential therapeutic modality for heart failure in DMD patients.

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.

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 Cytokines and Chemokines as Regulators of Skeletal Muscle Inflammation: Presenting the Case of Duchenne Muscular Dystrophy

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Boel De Paepe ◽  
Jan L. De Bleecker
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Current Knowledge ◽  
Damage Control ◽  
Inflammatory Cells ◽  
Muscle Disease ◽  
Fiber Damage ◽  
Cytokines And Chemokines ◽  
The Individual

Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed.

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.

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