Acute pathophysiological effects of muscle-expressed Dp71 transgene on normal and dystrophic mouse muscle

2003 ◽  
Vol 95 (5) ◽  
pp. 1861-1866 ◽  
Author(s):  
Sascha Wieneke ◽  
Peter Heimann ◽  
Sigalit Leibovitz ◽  
Uri Nudel ◽  
Harald Jockusch
Keyword(s):  
Muscular Dystrophy ◽  
Dystrophin Gene ◽  
Force Generation ◽  
Mdx Mouse ◽  
Mouse Muscle ◽  
Tetanic Force ◽  
Dystrophin Deficiency ◽  
Associated Proteins ◽  
Isometric Twitch ◽  
Tetanic Tension

products of the dystrophin gene range from the 427-kDa full-length dystrophin to the 70.8-kDa Dp71. Dp427 is expressed in skeletal muscle, where it links the actin cytoskeleton with the extracellular matrix via a complex of dystrophin-associated proteins (DAPs). Dystrophin deficiency disrupts the DAP complex and causes muscular dystrophy in humans and the mdx mouse. Dp71, the major nonmuscle product, consists of the COOH-terminal part of dystrophin, including the binding site for the DAP complex but lacks binding sites for microfilaments. Dp71 transgene (Dp71tg) expressed in mdx muscle restores the DAP complex but does not prevent muscle degeneration. In wild-type (WT) mouse muscle, Dp71tg causes a mild muscular dystrophy. In this study, we tested, using isolated extensor digitorum longus muscles, whether Dp71tg exerts acute influences on force generation and sarcolemmal stress resistance. In WT muscles, there was no effect on isometric twitch and tetanic force generation, but with a cytomegalovirus promotor-driven transgene, contraction with stretch led to sarcolemmal ruptures and irreversible loss of tension. In MDX muscle, Dp71tg reduced twitch and tetanic tension but did not aggravate sarcolemmal fragility. The adverse effects of Dp71 in muscle are probably due to its competition with dystrophin and utrophin (in MDX muscle) for binding to the DAP complex.

scholarly journals Cardiac Protection after Systemic Transplant of Dystrophin Expressing Chimeric (DEC) Cells to the mdx Mouse Model of Duchenne Muscular Dystrophy

2019 ◽  
Vol 15 (6) ◽  
pp. 827-841 ◽  
Author(s):  
Maria Siemionow ◽  
M. Malik ◽  
P. Langa ◽  
J. Cwykiel ◽  
S. Brodowska ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cardiac Function ◽  
Premature Death ◽  
Dystrophin Gene ◽  
Mdx Mouse ◽  
Cardiac Protection ◽  
Intraosseous Injection ◽  
Dystrophin Deficiency ◽  
Cardiac Muscles

Abstract Duchenne Muscular Dystrophy (DMD) is a progressive lethal disease caused by X-linked mutations of the dystrophin gene. Dystrophin deficiency clinically manifests as skeletal and cardiac muscle weakness, leading to muscle wasting and premature death due to cardiac and respiratory failure. Currently, no cure exists. Since heart disease is becoming a leading cause of death in DMD patients, there is an urgent need to develop new more effective therapeutic strategies for protection and improvement of cardiac function. We previously reported functional improvements correlating with dystrophin restoration following transplantation of Dystrophin Expressing Chimeric Cells (DEC) of myoblast origin in the mdx and mdx/scid mouse models. Here, we confirm positive effect of DEC of myoblast (MBwt/MBmdx) and mesenchymal stem cells (MBwt/MSCmdx) origin on protection of cardiac function after systemic DEC transplant. Therapeutic effect of DEC transplant (0.5 × 106) was assessed by echocardiography at 30 and 90 days after systemic-intraosseous injection to the mdx mice. At 90 days post-transplant, dystrophin expression in cardiac muscles of DEC injected mice significantly increased (15.73% ± 5.70 –MBwt/MBmdx and 5.22% ± 1.10 – MBwt/MSCmdx DEC) when compared to vehicle injected controls (2.01% ± 1.36) and, correlated with improved ejection fraction and fractional shortening on echocardiography. DEC lines of MB and MSC origin introduce a new promising approach based on the combined effects of normal myoblasts with dystrophin delivery capacities and MSC with immunomodulatory properties. Our study confirms feasibility and efficacy of DEC therapy on cardiac function and represents a novel therapeutic strategy for cardiac protection and muscle regeneration in DMD.

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 Investigation of the effect of taurine supplementation on muscle taurine content in the mdx mouse model of Duchenne muscular dystrophy using chemically specific synchrotron imaging

The Analyst ◽  
2020 ◽  
Vol 145 (22) ◽  
pp. 7242-7251
Author(s):  
Jessica R. Terrill ◽  
Samuel M. Webb ◽  
Peter G. Arthur ◽  
Mark J. Hackett
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Model ◽  
Muscle Tissue ◽  
Mdx Mouse ◽  
Taurine Supplementation ◽  
Mouse Muscle ◽  
Synchrotron Imaging

Sulfur K-edge XANES was used to quantify changes in the taurine content of mouse muscle tissue in a model of muscular dystrophy. The changes could be associated with markers of disease pathology that were revealed by classical H&E histology.

scholarly journals Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach

2007 ◽  
Vol 65 (1) ◽  
pp. 73-76 ◽  
Author(s):  
Aline Andrade Freund ◽  
Rosana Herminia Scola ◽  
Raquel Cristina Arndt ◽  
Paulo José Lorenzoni ◽  
Claudia Kamoy Kay ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscular Atrophy ◽  
Hot Spot ◽  
Dystrophin Gene ◽  
Becker Muscular Dystrophy ◽  
Congenital Myopathy ◽  
Specific Method ◽  
Dystrophin Deficiency ◽  
Muscle Biopsies ◽  
Female Carriers

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.

scholarly journals Electrical impedance myography for the in vivo and ex vivo assessment of muscular dystrophy (mdx ) mouse muscle

2014 ◽  
Vol 49 (6) ◽  
pp. 829-835 ◽  
Author(s):  
Jia Li ◽  
Tom R. Geisbush ◽  
Glenn D. Rosen ◽  
Jennifer Lachey ◽  
Aaron Mulivor ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Electrical Impedance ◽  
Ex Vivo ◽  
Mdx Mouse ◽  
Mouse Muscle

Association of dystrophin-related protein with dystrophin-associated proteins in mdx mouse muscle

Nature ◽  
1992 ◽  
Vol 360 (6404) ◽  
pp. 588-591 ◽  
Author(s):  
Kiichiro Matsumura ◽  
James M. Ervasti ◽  
Kay Ohlendieck ◽  
Steven D. Kahl ◽  
Kevin P. Campbell
Keyword(s):  
Mdx Mouse ◽  
Related Protein ◽  
Mouse Muscle ◽  
Associated Proteins

scholarly journals Several dystrophin-glycoprotein complex members are present in crude surface membranes but they are sodium dodecyl sulphate invisible in KCl-washed microsomes from mdx mouse muscle

2010 ◽  
Vol 15 (1) ◽  
Author(s):  
Stéphanie Daval ◽  
Chantal Rocher ◽  
Yan Cherel ◽  
Elisabeth Rumeur
Keyword(s):  
Muscular Dystrophy ◽  
Core Protein ◽  
Surface Membrane ◽  
Sodium Dodecyl ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Mouse Muscle ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

AbstractThe dystrophin-glycoprotein complex (DGC) is a large trans-sarcolemmal complex that provides a linkage between the subsarcolemmal cytoskeleton and the extracellular matrix. In skeletal muscle, it consists of the dystroglycan, sarcoglycan and cytoplasmic complexes, with dystrophin forming the core protein. The DGC has been described as being absent or greatly reduced in dystrophin-deficient muscles, and this lack is considered to be involved in the dystrophic phenotype. Such a decrease in the DGC content was observed in dystrophin-deficient muscle from humans with muscular dystrophy and in mice with X-linked muscular dystrophy (mdx mice). These deficits were observed in total muscle homogenates and in partially membrane-purified muscle fractions, the so-called KCl-washed microsomes. Here, we report that most of the proteins of the DGC are actually present at normal levels in the mdx mouse muscle plasma membrane. The proteins are detected in dystrophic animal muscles when the immunoblot assay is performed with crude surface membrane fractions instead of the usually employed KCl-washed microsomes. We propose that these proteins form SDS-insoluble membrane complexes when dystrophin is absent.

scholarly journals Dystrophin-associated proteins are greatly reduced in skeletal muscle from mdx mice.

1991 ◽  
Vol 115 (6) ◽  
pp. 1685-1694 ◽  
Author(s):  
K Ohlendieck ◽  
K P Campbell
Keyword(s):  
Skeletal Muscle ◽  
Immunoblot Analysis ◽  
Protein Product ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Normal Density ◽  
Mouse Muscle ◽  
Glycoprotein Complex ◽  
Associated Proteins ◽  
Dy Mouse

Dystrophin, the protein product of the human Duchenne muscular dystrophy gene, exists in skeletal muscle as a large oligomeric complex that contains four glycoproteins of 156, 50, 43, and 35 kD and a protein of 59 kD. Here, we investigated the relative abundance of each of the components of the dystrophin-glycoprotein complex in skeletal muscle from normal and mdx mice, which are missing dystrophin. Immunoblot analysis using total muscle membranes from control and mdx mice of ages 1 d to 30 wk found that all of the dystrophin-associated proteins were greatly reduced (80-90%) in mdx mouse skeletal muscle. The specificity of the loss of the dystrophin-associated glycoproteins was demonstrated by the finding that the major glycoprotein composition of skeletal muscle membranes from normal and mdx mice was identical. Furthermore, skeletal muscle membranes from the dystrophic dy/dy mouse exhibited a normal density of dystrophin and dystrophin-associated proteins. Immunofluorescence microscopy confirmed the results from the immunoblot analysis and showed a drastically reduced density of dystrophin-associated proteins in mdx muscle cryosections compared with normal and dy/dy mouse muscle. Therefore, our results demonstrate that all of the dystrophin-associated proteins are significantly reduced in mdx skeletal muscle and suggest that the loss of dystrophin-associated proteins is due to the absence of dystrophin and not due to secondary effects of muscle fiber degradation.

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