scholarly journals Membrane Targeting and Stabilization of Sarcospan Is Mediated by the Sarcoglycan Subcomplex

1999 ◽  
Vol 145 (1) ◽  
pp. 153-165 ◽  
Author(s):  
Rachelle H. Crosbie ◽  
Connie S. Lebakken ◽  
Kathleen H. Holt ◽  
David P. Venzke ◽  
Volker Straub ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Muscular Dystrophy ◽  
Genetic Mutations ◽  
Myotendinous Junction ◽  
Normal Muscle ◽  
Glycoprotein Complex ◽  
Muscle Plasma Membrane ◽  
Dystrophin Glycoprotein Complex ◽  
And Function ◽  
Dystrophin Glycoprotein

The dystrophin–glycoprotein complex (DGC) is a multisubunit complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. The proteins of the DGC are structurally organized into distinct subcomplexes, and genetic mutations in many individual components are manifested as muscular dystrophy. We recently identified a unique tetraspan-like dystrophin-associated protein, which we have named sarcospan (SPN) for its multiple sarcolemma spanning domains (Crosbie, R.H., J. Heighway, D.P. Venzke, J.C. Lee, and K.P. Campbell. 1997. J. Biol. Chem. 272:31221–31224). To probe molecular associations of SPN within the DGC, we investigated SPN expression in normal muscle as a baseline for comparison to SPN's expression in animal models of muscular dystrophy. We show that, in addition to its sarcolemma localization, SPN is enriched at the myotendinous junction (MTJ) and neuromuscular junction (NMJ), where it is a component of both the dystrophin– and utrophin–glycoprotein complexes. We demonstrate that SPN is preferentially associated with the sarcoglycan (SG) subcomplex, and this interaction is critical for stable localization of SPN to the sarcolemma, NMJ, and MTJ. Our experiments indicate that assembly of the SG subcomplex is a prerequisite for targeting SPN to the sarcolemma. In addition, the SG– SPN subcomplex functions to stabilize α-dystroglycan to the muscle plasma membrane. Taken together, our data provide important information about assembly and function of the SG–SPN subcomplex.

Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex

2000 ◽  
Vol 113 (14) ◽  
pp. 2535-2544 ◽  
Author(s):  
A.A. Hack ◽  
M.Y. Lam ◽  
L. Cordier ◽  
D.I. Shoturma ◽  
C.T. Ly ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Muscular Dystrophy ◽  
Eccentric Contraction ◽  
Muscle Membrane ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Alpha Beta ◽  
And Function ◽  
Dystrophin Glycoprotein

Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of (gamma)- and (delta)-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.

scholarly journals Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle

2006 ◽  
Vol 290 (2) ◽  
pp. C411-C419 ◽  
Author(s):  
Elisabeth R. Barton
Keyword(s):  
Skeletal Muscle ◽  
Mechanical Load ◽  
Eccentric Contraction ◽  
Eccentric Contractions ◽  
Normal Muscle ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Severe Pathology ◽  
Murine Skeletal Muscle ◽  
Dystrophin Glycoprotein

Loss of the dystrophin glycoprotein complex (DGC) or a subset of its components can lead to muscular dystrophy. However, the patterns of symptoms differ depending on which proteins are affected. Absence of dystrophin leads to loss of the entire DGC and is associated with susceptibility to contractile injury. In contrast, muscles lacking γ-sarcoglycan (γ-SG) display little mechanical fragility and still develop severe pathology. Animals lacking dystrophin or γ-SG were used to identify DGC components critical for sensing dynamic mechanical load. Extensor digitorum longus muscles from 7-wk-old normal (C57), dystrophin- null ( mdx), and γ-SG-null ( gsg−/−) mice were subjected to a series of eccentric contractions, after which ERK1/2 phosphorylation levels were determined. At rest, both dystrophic strains had significantly higher ERK1 phosphorylation, and gsg−/− muscle also had heightened ERK2 phosphorylation compared with wild-type controls. Eccentric contractions produced a significant and transient increase in ERK1/2 phosphorylation in normal muscle, whereas the mdx strain displayed no significant proportional change of ERK1/2 phosphorylation after eccentric contraction. Muscles from gsg−/− mice had no significant increase in ERK1 phosphorylation; however, ERK2 phosphorylation was more robust than in C57 controls. The reduction in mechanically induced ERK1 phosphorylation in gsg−/− muscle was not dependent on age or severity of phenotype, because muscle from both young and old (age 20 wk) animals exhibited a reduced response. Immunoprecipitation experiments revealed that γ-SG was phosphorylated in normal muscle after eccentric contractions, indicating that members of the DGC are modified in response to mechanical perturbation. This study provides evidence that the SGs are involved in the transduction of mechanical information in skeletal muscle, potentially unique from the entire DGC.

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.

scholarly journals Sarcospan-Deficient Mice Maintain Normal Muscle Function

2000 ◽  
Vol 20 (5) ◽  
pp. 1669-1677 ◽  
Author(s):  
Connie S. Lebakken ◽  
David P. Venzke ◽  
Ronald F. Hrstka ◽  
Christina M. Consolino ◽  
John A. Faulkner ◽  
...  
Keyword(s):  
Muscle Function ◽  
Normal Force ◽  
Membrane Component ◽  
Normal Muscle ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Evans Blue Uptake ◽  
Dystrophin Glycoprotein ◽  
Deficient Mice ◽  
Sarcolemmal Integrity

ABSTRACT Sarcospan is an integral membrane component of the dystrophin-glycoprotein complex (DGC) found at the sarcolemma of striated and smooth muscle. The DGC plays important roles in muscle function and viability as evidenced by defects in components of the DGC, which cause muscular dystrophy. Sarcospan is unique among the components of the complex in that it contains four transmembrane domains with intracellular N- and C-terminal domains and is a member of the tetraspan superfamily of proteins. Sarcospan is tightly linked to the sarcoglycans, and together these proteins form a subcomplex within the DGC. Stable expression of sarcospan at the sarcolemma is dependent upon expression of the sarcoglycans. Here we describe the generation and analysis of mice carrying a null mutation in the Sspngene. Surprisingly, the Sspn-deficient muscle maintains expression of other components of the DGC at the sarcolemma, and no gross histological abnormalities of muscle from the mice are observed. The Sspn-deficient muscle maintains sarcolemmal integrity as determined by serum creatine kinase and Evans blue uptake assays, and the Sspn-deficient muscle maintains normal force and power generation capabilities. These data suggest either that sarcospan is not required for normal DGC function or that theSspn-deficient muscle is compensating for the absence of sarcospan, perhaps by utilizing another protein to carry out its function.

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
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