scholarly journals Dystrophin colocalizes with beta-spectrin in distinct subsarcolemmal domains in mammalian skeletal muscle

1992 ◽  
Vol 117 (5) ◽  
pp. 997-1005 ◽  
Author(s):  
GA Porter ◽  
GM Dmytrenko ◽  
JC Winkelmann ◽  
RJ Bloch
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Muscular Dystrophy ◽  
Longitudinal Axis ◽  
Mdx Mouse ◽  
Mammalian Skeletal Muscle ◽  
Contractile Apparatus ◽  
Structural Protein ◽  
Immunofluorescence Studies ◽  
Duchenne's Muscular Dystrophy

Duchenne's muscular dystrophy (DMD) is caused by the absence or drastic decrease of the structural protein, dystrophin, and is characterized by sarcolemmal lesions in skeletal muscle due to the stress of contraction. Dystrophin has been localized to the sarcolemma, but its organization there is not known. We report immunofluorescence studies which show that dystrophin is concentrated, along with the major muscle isoform of beta-spectrin, in three distinct domains at the sarcolemma: in elements overlying both I bands and M lines, and in occasional strands running along the longitudinal axis of the myofiber. Vinculin, which has previously been found at the sarcolemma overlying the I bands and in longitudinal strands, was present in the same three structures as spectrin and dystrophin. Controls demonstrated that the labeling was intracellular. Comparison to labeling of the lipid bilayer and of the extracellular matrix showed that the labeling for spectrin and dystrophin is associated with the intact sarcolemma and is not a result of processing artifacts. Dystrophin is not required for this lattice-like organization, as similar domains containing spectrin but not dystrophin are present in muscle from the mdx mouse and from humans with Duchenne's muscular dystrophy. We discuss the possibility that dystrophin and spectrin, along with vinculin, may function to link the contractile apparatus to the sarcolemma of normal skeletal muscle.

scholarly journals Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1

2009 ◽  
Vol 20 (1) ◽  
pp. 146-152 ◽  
Author(s):  
Michelle S. Steen ◽  
Marvin E. Adams ◽  
Yan Tesch ◽  
Stanley C. Froehner
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Mdx Mouse ◽  
Lysosomal Storage ◽  
Transgenic Expression ◽  
New Therapeutic Approaches ◽  
Human Disorders ◽  
Niemann Pick ◽  
Dystrophin Protein

Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment

2006 ◽  
Vol 290 (2) ◽  
pp. C577-C582 ◽  
Author(s):  
Stefania Assereto ◽  
Silvia Stringara ◽  
Federica Sotgia ◽  
Gloria Bonuccelli ◽  
Aldobrando Broccolini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Proteasome Inhibitor ◽  
Becker Muscular Dystrophy ◽  
Culture Conditions ◽  
Mdx Mouse ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Novel Method ◽  
Dystrophin Glycoprotein

In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, β-dystroglycan, and α-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663–1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in humans.

scholarly journals BETs inhibition attenuates oxidative stress and preserves muscle integrity in Duchenne muscular dystrophy

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marco Segatto ◽  
Roberta Szokoll ◽  
Raffaella Fittipaldi ◽  
Cinzia Bottino ◽  
Lorenzo Nevi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mdx Mouse ◽  
Early Event ◽  
Dystrophic Muscle ◽  
Protein Levels ◽  
Bet Inhibitors ◽  
Ros Metabolism

AbstractDuchenne muscular dystrophy (DMD) affects 1 in 3500 live male births. To date, there is no effective cure for DMD, and the identification of novel molecular targets involved in disease progression is important to design more effective treatments and therapies to alleviate DMD symptoms. Here, we show that protein levels of the Bromodomain and extra-terminal domain (BET) protein BRD4 are significantly increased in the muscle of the mouse model of DMD, the mdx mouse, and that pharmacological inhibition of the BET proteins has a beneficial outcome, tempering oxidative stress and muscle damage. Alterations in reactive oxygen species (ROS) metabolism are an early event in DMD onset and they are tightly linked to inflammation, fibrosis, and necrosis in skeletal muscle. By restoring ROS metabolism, BET inhibition ameliorates these hallmarks of the dystrophic muscle, translating to a beneficial effect on muscle function. BRD4 direct association to chromatin regulatory regions of the NADPH oxidase subunits increases in the mdx muscle and JQ1 administration reduces BRD4 and BRD2 recruitment at these regions. JQ1 treatment reduces NADPH subunit transcript levels in mdx muscles, isolated myofibers and DMD immortalized myoblasts. Our data highlight novel functions of the BET proteins in dystrophic skeletal muscle and suggest that BET inhibitors may ameliorate the pathophysiology of DMD.

scholarly journals Clinical and Experimental Results on Cardiac Troponin Expression in Duchenne Muscular Dystrophy

2001 ◽  
Vol 47 (3) ◽  
pp. 451-458 ◽  
Author(s):  
Angelika Hammerer-Lercher ◽  
Petra Erlacher ◽  
Reginald Bittner ◽  
Rudolf Korinthenberg ◽  
Daniela Skladal ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Western Blot ◽  
Blot Analysis ◽  
Cardiac Troponin ◽  
Western Blot Analysis ◽  
Clinical Evidence ◽  
Mdx Mouse ◽  
Muscle Biopsies

Abstract Background: Because of controversial earlier studies, the purpose of this study was to provide novel experimental and additional clinical data regarding the possible reexpression of cardiac troponin T (cTnT) in regenerating skeletal muscle in Duchenne muscular dystrophy (DMD). Methods: Plasma from 14 patients (mean age, 7.5 years; range, 5.7–19.4 years) with DMD was investigated for creatine kinase (CK), the CK MB isoenzyme (CKMB), cTnT and cardiac troponin I (cTnI), and myoglobin. cTnT concentrations were measured by an ELISA (second-generation assay; Roche) using the ES 300 Analyzer. cTnI, myoglobin, and CKMB were measured by an ELISA using the ACCESS System (Beckman Diagnostics). Troponin isoform expression was studied by Western blot analysis in remnants of skeletal muscle biopsies of three patients with DMD and in an animal model of DMD (mdx mice; n = 6). Results: There was no relation of cTnT and cTnI to clinical evidence for cardiac failure. cTnI concentrations remained below the upper reference limit in all patients. cTnT was increased (median, 0.11 μg/L; range, 0.06–0.16 μg/L) in 50% of patients. The only significant correlation was found for CK (median, 3938 U/L; range, 2763–5030 U/L) with age (median, 7.5 years; range, 6.8–10.9 years; r = −0.762; P = 0.042). Western blot analysis of human or mouse homogenized muscle specimens showed no evidence for cardiac TnT and cTnI expression, despite strong signals for skeletal muscle troponin isoforms. Conclusions: We found no evidence for cTnT reexpression in human early-stage DMD and in mdx mouse skeletal muscle biopsies. Discrepancies of cTnT and cTnI in plasma samples of DMD patients were found, but neither cTnT nor cTnI plasma concentrations were related with other clinical evidence for cardiac involvement.

scholarly journals The D2.mdx mouse as a preclinical model of the skeletal muscle pathology associated with Duchenne muscular dystrophy

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
David W. Hammers ◽  
Cora C. Hart ◽  
Michael K. Matheny ◽  
Lillian A. Wright ◽  
Megan Armellini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Muscle Pathology ◽  
Mdx Mouse ◽  
Preclinical Model

scholarly journals Lmo7 is dispensable for skeletal muscle and cardiac function

2015 ◽  
Vol 309 (7) ◽  
pp. C470-C479 ◽  
Author(s):  
Dieu Hung Lao ◽  
Mary C. Esparza ◽  
Shannon N. Bremner ◽  
Indroneal Banerjee ◽  
Jianlin Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Cardiac Function ◽  
Cardiac Muscle ◽  
Mapk Pathway ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Mouse Line

Emery-Dreifuss muscular dystrophy (EDMD) is a degenerative disease primarily affecting skeletal muscles in early childhood as well as cardiac muscle at later stages. EDMD is caused by a number of mutations in genes encoding proteins associated with the nuclear envelope (e.g., Emerin, Lamin A/C, and Nesprin). Recently, a novel protein, Lim-domain only 7 ( lmo7) has been reported to play a role in the molecular pathogenesis of EDMD. Prior in vitro and in vivo studies suggested the intriguing possibility that Lmo7 plays a role in skeletal or cardiac muscle pathophysiology. To further understand the in vivo role of Lmo7 in striated muscles, we generated a novel Lmo7-null ( lmo7−/−) mouse line. Using this mouse line, we examined skeletal and cardiac muscle physiology, as well as the role of Lmo7 in a model of muscular dystrophy and regeneration using the dystrophin-deficient mdx mouse model. Our results demonstrated that lmo7−/− mice had no abnormalities in skeletal muscle morphology, physiological function, or regeneration. Cardiac function was also unaffected. Moreover, we found that ablation of lmo7 in mdx mice had no effect on the observed myopathy and muscular regeneration exhibited by mdx mice. Molecular analyses also showed no changes in dystrophin complex factors, MAPK pathway components, and Emerin levels in lmo7 knockout mice. Taken together, we conclude that Lmo7 is dispensable for skeletal muscle and cardiac physiology and pathophysiology.

scholarly journals Membrane glucocorticoid receptors are localised in the extracellular matrix and signal through the MAPK pathway in mammalian skeletal muscle fibres

2015 ◽  
Vol 593 (12) ◽  
pp. 2679-2692 ◽  
Author(s):  
Simona Boncompagni ◽  
Lewis Arthurton ◽  
Eugene Akujuru ◽  
Timothy Pearson ◽  
Dietmar Steverding ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Glucocorticoid Receptors ◽  
Mapk Pathway ◽  
Muscle Fibres ◽  
Mammalian Skeletal Muscle ◽  
Skeletal Muscle Fibres

Hematopoietic stem cell transplantation does not restore dystrophin expression in Duchenne muscular dystrophy dogs

Blood ◽  
2004 ◽  
Vol 104 (13) ◽  
pp. 4311-4318 ◽  
Author(s):  
Chiara Dell'Agnola ◽  
Zejing Wang ◽  
Rainer Storb ◽  
Stephen J. Tapscott ◽  
Christian S. Kuhr ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cell Transplantation ◽  
Hematopoietic Cell ◽  
Mdx Mouse ◽  
Hematopoietic Stem ◽  
Bone Marrow Derived Cells ◽  
Donor Muscle

Abstract Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene on the X-chromosome that result in skeletal and cardiac muscle damage and premature death. Studies in mice, including the mdx mouse model of DMD, have demonstrated that circulating bone marrow–derived cells can participate in skeletal muscle regeneration, but the potential clinical utility of treating human DMD by allogeneic marrow transplantation from a healthy donor remains unknown. To assess whether allogeneic hematopoietic cell transplantation (HCT) provides clinically relevant levels of donor muscle cell contribution in dogs with canine X-linked muscular dystrophy (c-xmd), 7 xmd dogs were given hematopoietic cell (HC) transplants from nonaffected littermates. Compared with the pretransplantation baseline, the number of dystrophin-positive fibers and the amount of wild-type dystrophin RNA did not increase after HCT, with observation periods ranging from 28 to 417 days. Similar results were obtained when the recipient dogs were given granulocyte colony-stimulating factor (G-CSF) after their initial transplantation to mobilize the cells. Despite successful allogeneic HCT and a permissive environment for donor muscle engraftment, there was no detectable contribution of bone marrow–derived cells to either skeletal muscle or muscle precursor cells assayed by clonal analyses at a level of sensitivity that should detect as little as 0.1% donor contribution.

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