Sarcospan reduces dystrophic pathology: stabilization of the utrophin–glycoprotein complex

Mutations in the dystrophin gene cause Duchenne muscular dystrophy and result in the loss of dystrophin and the entire dystrophin–glycoprotein complex (DGC) from the sarcolemma. We show that sarcospan (SSPN), a unique tetraspanin-like component of the DGC, ameliorates muscular dystrophy in dystrophin-deficient mdx mice. SSPN stabilizes the sarcolemma by increasing levels of the utrophin–glycoprotein complex (UGC) at the extrasynaptic membrane to compensate for the loss of dystrophin. Utrophin is normally restricted to the neuromuscular junction, where it replaces dystrophin to form a functionally analogous complex. SSPN directly interacts with the UGC and functions to stabilize utrophin protein without increasing utrophin transcription. These findings reveal the importance of protein stability in the prevention of muscular dystrophy and may impact the future design of therapeutics for muscular dystrophies.

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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

Cellular & Molecular Biology Letters ◽

10.2478/s11658-009-0039-8 ◽

2010 ◽

Vol 15 (1) ◽

Cited By ~ 2

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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Caveolin-3: A Causative Process of Chicken Muscular Dystrophy

Biomolecules ◽

10.3390/biom10091206 ◽

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.

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382. In Utero Intramuscular Delivery of a High-Capacity Adenoviral Vector Carrying a Full-Length Murine Dystrophin cDNA Provides Functional Benefit and Reassembly of the Dystrophin-Glycoprotein Complex in Hind Limb Muscles of mdx Mice

Molecular Therapy ◽

10.1016/j.ymthe.2004.06.919 ◽

2004 ◽

Vol 9 ◽

pp. S146

Keyword(s):

Adenoviral Vector ◽

Hind Limb ◽

High Capacity ◽

In Utero ◽

Mdx Mice ◽

Glycoprotein Complex ◽

Functional Benefit ◽

Dystrophin Glycoprotein Complex ◽

Dystrophin Glycoprotein ◽

Intramuscular Delivery

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

AJP Cell Physiology ◽

10.1152/ajpcell.00434.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. C577-C582 ◽

Cited By ~ 45

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.

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Faculty Opinions recommendation of Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8250.346553 ◽

2005 ◽

Author(s):

Carlo Reggiani

Keyword(s):

Muscular Dystrophy ◽

Cancer Cachexia ◽

Glycoprotein Complex ◽

Regulatory Link ◽

Dystrophin Glycoprotein Complex ◽

Dystrophin Glycoprotein

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

Circulation Research ◽

10.1161/res.121.suppl_1.78 ◽

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.

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