scholarly journals Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yoshihiro Ujihara ◽  
Motoi Kanagawa ◽  
Satoshi Mohri ◽  
Satomi Takatsu ◽  
Kazuhiro Kobayashi ◽  
...  
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Developmental Stages ◽  
Colchicine Treatment ◽  
Causative Gene ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Microtubule Networks ◽  
Molecular Pathomechanisms

AbstractHeart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention.

scholarly journals Reduced plasticity and microtubule densification in muscular dystrophy-related cardiomyopathy

2021 ◽  
Vol 154 (9) ◽  
Author(s):  
Yuki Katanosaka
Keyword(s):  
Heart Failure ◽  
Muscular Dystrophy ◽  
Cardiac Dysfunction ◽  
Developmental Stages ◽  
Myocardial Dysfunction ◽  
Colchicine Treatment ◽  
Contractile Dysfunction ◽  
Causative Gene ◽  
Hypertrophic Response ◽  
Deficient Mice

The dystrophin–glycoprotein complex (DGC) links the intracellular cytoskeleton to the extracellular basement membrane, thereby providing structural support for the sarcolemma. Many patients with muscular dystrophies, particularly those with defects in cardiomyopathies with chamber dilation and myocardial dysfunction. Heart failure is the major cause of death for muscular dystrophy patients; however, the molecular pathomechanism remains unknown. Here, I show the detailed molecular pathogenesis of muscular dystrophy–associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced the glycosylation of α-dystroglycan and the expression of DGC proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that the physiological contribution of DGC proteins in the heart increases after 6 mo of age. In addition, Fktn-deficient mice maintain normal cardiac function at young age, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. Young Fktn-deficient mice did not show a compensative hypertrophic response to hemodynamic stress and quickly developed heart failure with chamber dilation and contractile dysfunction. In these mice, Ca2+-calcineurin signaling was already elevated under physiological conditions, and MEF2-HDAC axes essential for the hypertrophic response were unable to function under stress conditions. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi–microtubule networks, which were ameliorated with colchicine treatment. Microarray analysis in control and Fktn-deficient hearts suggest that elimination of Fktn impacts the expression profile of Golgi-related genes, and that the pathological mechanism of cardiac dysfunction induced by Fktn elimination partly overlaps with that of neurodegenerative disease. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and, thus, the results may lead to strategies for intervention.

Removal of dystroglycan causes severe muscular dystrophy in zebrafish embryos

Development ◽  
2002 ◽  
Vol 129 (14) ◽  
pp. 3505-3512 ◽  
Author(s):  
Michael J. Parsons ◽  
Isabel Campos ◽  
Elizabeth M. A. Hirst ◽  
Derek L. Stemple
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Muscular Dystrophy ◽  
Muscle Cells ◽  
Laminin Receptor ◽  
Central Component ◽  
Zebrafish Embryos ◽  
Term Survival ◽  
Α Subunit ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex

Muscular dystrophy is frequently caused by disruption of the dystrophin-glycoprotein complex (DGC), which links muscle cells to the extracellular matrix. Dystroglycan, a central component of the DGC, serves as a laminin receptor via its extracellular α subunit, and interacts with dystrophin (and thus the actin cytoskeleton) through its integral membrane β subunit. We have removed the function of dystroglycan in zebrafish embryos. In contrast to mouse, where dystroglycan mutations lead to peri-implantation lethality, dystroglycan is dispensable for basement membrane formation during early zebrafish development. At later stages, however, loss of dystroglycan leads to a disruption of the DGC, concurrent with loss of muscle integrity and necrosis. In addition, we find that loss of the DGC leads to loss of sarcomere and sarcoplasmic reticulum organisation. The DGC is required for long-term survival of muscle cells in zebrafish, but is dispensable for muscle formation. Dystroglycan or the DGC is also required for normal sarcomere and sarcoplasmic reticulum organisation. Because zebrafish embryos lacking dystroglycan share several characteristics with human muscular dystrophy, they should serve as a useful model for the disease. In addition, knowing the dystroglycan null phenotype in zebrafish will facilitate the isolation of other molecules involved in muscular dystrophy pathogenesis.

scholarly journals Caveolin-3: A Causative Process of Chicken Muscular Dystrophy

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1206
Author(s):  
Tateki Kikuchi
Keyword(s):  
Muscular Dystrophy ◽  
Missense Mutation ◽  
Ubiquitin Ligase ◽  
Core Protein ◽  
Ubiquitin Protein Ligase ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Slow Twitch ◽  
Fast Twitch ◽  
Dystrophin Glycoprotein

The etiology of chicken muscular dystrophy is the synthesis of aberrant WW domain containing E3 ubiquitin-protein ligase 1 (WWP1) protein made by a missense mutation of WWP1 gene. The β-dystroglycan that confers stability to sarcolemma was identified as a substrate of WWP protein, which induces the next molecular collapse. The aberrant WWP1 increases the ubiquitin ligase-mediated ubiquitination following severe degradation of sarcolemmal and cytoplasmic β-dystroglycan, and an erased β-dystroglycan in dystrophic αW fibers will lead to molecular imperfection of the dystrophin-glycoprotein complex (DGC). The DGC is a core protein of costamere that is an essential part of force transduction and protects the muscle fibers from contraction-induced damage. Caveolin-3 (Cav-3) and dystrophin bind competitively to the same site of β-dystroglycan, and excessive Cav-3 on sarcolemma will block the interaction of dystrophin with β-dystroglycan, which is another reason for the disruption of the DGC. It is known that fast-twitch glycolytic fibers are more sensitive and vulnerable to contraction-induced small tears than slow-twitch oxidative fibers under a variety of diseased conditions. Accordingly, the fast glycolytic αW fibers must be easy with rapid damage of sarcolemma corruption seen in chicken muscular dystrophy, but the slow oxidative fibers are able to escape from these damages.

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.

Abstract 78: Hippo Pathway and Dystrophin Glycoprotein Complex Regulate Cardiomyocyte Proliferation

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Yuka Morikawa ◽  
Todd Heallen ◽  
John Leach ◽  
Yang Xiao ◽  
James Martin
Keyword(s):  
Cell Cycle ◽  
Muscular Dystrophy ◽  
Hippo Pathway ◽  
Myocardial Damage ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
The Hippo Pathway ◽  
Dystrophin Glycoprotein

Regeneration of mammalian heart is limited due to the extremely low renewal rate of cardiomyocytes and their inability to reenter the cell cycle. The Hippo pathway controls heart size during development and represses postnatal heart regeneration by repressing cardiomyocyte proliferation. Our approach for activating adult heart regeneration is to uncover the mechanisms responsible for repression of cardiomyocyte proliferation. We have previously found that deletion of Salv, a modulator of the Hippo pathway, results in myocardial damage repair in postnatal and adult hearts. Deletion of Salv results in activation of the transcription factor, Yap, which positively regulates cytoskeleton and cell cycle genes. We also found that the components of dystrophin glycoprotein complex (DGC) are the target of Yap and DGC regulates heart regeneration. The dystrophin glycoprotein complex (DGC) is essential for muscle maintenance by anchoring the cytoskeleton and extracellular matrix. Disruption of the DGC results in muscular dystrophies, including Duchenne muscular dystrophy, resulting in both skeletal and cardiac myopathies. To explore the connection between DGC and the Hippo pathway, we conditionally deleted Salv in the mdx background, a mouse model of muscular dystrophy. We found that simultaneous disruption of the DGC and the Hippo pathway leads an increased cardiomyocyte proliferation after heart damage. This is associated with increased activity of Yap, suggesting DGC negatively regulate Yap to repress proliferation. We also found that one of the components DGC, dystroglycan directly binds Yap and anchors to the membrane. Our findings provide new insights into the mechanisms leading to heart repair through proliferation of endogenous cardiomyocytes.

A novel FKRP mutation in congenital muscular dystrophy disrupts the dystrophin glycoprotein complex

2007 ◽  
Vol 17 (4) ◽  
pp. 285-289 ◽  
Author(s):  
Heather MacLeod ◽  
Peter Pytel ◽  
Robert Wollmann ◽  
Ewa Chelmicka-Schorr ◽  
Kenneth Silver ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Congenital Muscular Dystrophy ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

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.

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