Expression of the dystrophin-glycoprotein complex is a marker for human airway smooth muscle phenotype maturation

2008 ◽  
Vol 294 (1) ◽  
pp. L57-L68 ◽  
Author(s):  
Pawan Sharma ◽  
Thai Tran ◽  
Gerald L. Stelmack ◽  
Karol McNeill ◽  
Reinoud Gosens ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Serum Deprivation ◽  
Muscle Physiology ◽  
Smooth Muscle Tissue ◽  
Glycoprotein Complex ◽  
Contractile Phenotype ◽  
Dystrophin Glycoprotein Complex ◽  
Health And Disease ◽  
Dystrophin Glycoprotein

Airway smooth muscle (ASM) cells may contribute to asthma pathogenesis through their capacity to switch between a synthetic/proliferative and a contractile phenotype. The multimeric dystrophin-glycoprotein complex (DGC) spans the sarcolemma, linking the actin cytoskeleton and extracellular matrix. The DGC is expressed in smooth muscle tissue, but its functional role is not fully established. We tested whether contractile phenotype maturation of human ASM is associated with accumulation of DGC proteins. We compared subconfluent, serum-fed cultures and confluent cultures subjected to serum deprivation, which express a contractile phenotype. Western blotting confirmed that β-dystroglycan, β-, δ-, and ε-sarcoglycan, and dystrophin abundance increased six- to eightfold in association with smooth muscle myosin heavy chain (smMHC) and calponin accumulation during 4-day serum deprivation. Immunocytochemistry showed that the accumulation of DGC subunits was specifically localized to a subset of cells that exhibit robust staining for smMHC. Laminin competing peptide (YIGSR, 1 μM) and phosphatidylinositol 3-kinase (PI3K) inhibitors (20 μM LY-294002 or 100 nM wortmannin) abrogated the accumulation of smMHC, calponin, and DGC proteins. These studies demonstrate that the accumulation of DGC is an integral feature for phenotype maturation of human ASM cells. This provides a strong rationale for future studies investigating the role of the DGC in ASM smooth muscle physiology in health and disease.

Characterization of the dystrophin–glycoprotein complex in airway smooth muscle: role of δ-sarcoglycan in airway responsiveness

2015 ◽  
Vol 93 (3) ◽  
pp. 195-202 ◽  
Author(s):  
Pawan Sharma ◽  
Aruni Jha ◽  
Gerald L. Stelmack ◽  
Karen Detillieux ◽  
Sujata Basu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Lung Function ◽  
Airway Smooth Muscle ◽  
Caveolin 1 ◽  
Glycoprotein Complex ◽  
Airway Mechanics ◽  
Age Dependent ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

The dystrophin–glycoprotein complex (DGC) is an integral part of caveolae microdomains, and its interaction with caveolin-1 is essential for the phenotype and functional properties of airway smooth muscle (ASM). The sarcoglycan complex provides stability to the dystroglycan complex, but its role in ASM contraction and lung physiology in not understood. We tested whether δ-sarcoglycan (δ-SG), through its interaction with the DGC, is a determinant of ASM contraction ex vivo and airway mechanics in vivo. We measured methacholine (MCh)-induced isometric contraction and airway mechanics in δ-SG KO and wild-type mice. Last, we performed immunoblotting and transmission electron microscopy to assess DGC protein expression and the ultrastructural features of tracheal smooth muscle. Our results reveal an age-dependent reduction in the MCh-induced tracheal isometric force and significant reduction in airway resistance at high concentrations of MCh (50.0 mg/mL) in δ-SG KO mice. The changes in contraction and lung function correlated with decreased caveolin-1 and β-dystroglycan abundance, as well as an age-dependent loss of caveolae in the cell membrane of tracheal smooth muscle in δ-SG KO mice. Collectively, these results confirm and extend understanding of a functional role for the DGC in the contractile properties of ASM and demonstrate that this results in altered lung function in vivo.

scholarly journals Sarcoglycan Subcomplex Expression in Normal Human Smooth Muscle

2007 ◽  
Vol 55 (8) ◽  
pp. 831-843 ◽  
Author(s):  
Giuseppe Anastasi ◽  
Giuseppina Cutroneo ◽  
Antonina Sidoti ◽  
Carmen Rinaldi ◽  
Daniele Bruschetta ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Muscle Type ◽  
Common Assumption ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Normal Human ◽  
First Time ◽  
Dystrophin Glycoprotein ◽  
Lower Expression

The sarcoglycan complex (SGC) is a multimember transmembrane complex interacting with other members of the dystrophin–glycoprotein complex (DGC) to provide a mechanosignaling connection from the cytoskeleton to the extracellular matrix. The SGC consists of four proteins (α, β, γ, and δ). A fifth sarcoglycan subunit, ∊-sarcoglycan, shows a wider tissue distribution. Recently, a novel sarcoglycan, the ζ-sarcoglycan, has been identified. All reports about the structure of SGC showed a common assumption of a tetrameric arrangement of sarcoglycans. Addressing this issue, our immunofluorescence and molecular results showed, for the first time, that all sarcoglycans are always detectable in all observed samples. Therefore, one intriguing possibility is the existence of a pentameric or hexameric complex considering ζ-sarcoglycan of SGC, which could present a higher or lower expression of a single sarcoglycan in conformity with muscle type—skeletal, cardiac, or smooth—or also in conformity with the origin of smooth muscle. (J Histochem Cytochem 55:831–843, 2007)

The association of caveolae, actin, and the dystrophin–glycoprotein complex: a role in smooth muscle phenotype and function?

2005 ◽  
Vol 83 (10) ◽  
pp. 877-891 ◽  
Author(s):  
Andrew J Halayko ◽  
Gerald L Stelmack
Keyword(s):  
Smooth Muscle ◽  
Structural Proteins ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Contractile Apparatus ◽  
Caveolin 1 ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
And Function ◽  
Dystrophin Glycoprotein

Smooth muscle cells exhibit phenotypic and mechanical plasticity. During maturation, signalling pathways controlling actin dynamics modulate contractile apparatus-associated gene transcription and contractile apparatus remodelling resulting from length change. Differentiated myocytes accumulate abundant caveolae that evolve from the structural association of lipid rafts with caveolin-1, a protein with domains that confer unique functional properties. Caveolae and caveolin-1 modulate and participate in receptor-mediated signalling, and thus contribute to functional diversity of phenotypically similar myocytes. In mature smooth muscle, caveolae are partitioned into discrete linear domains aligned with structural proteins that tether actin to the extracellular matrix. Caveolin-1 binds with β-dystroglycan, a subunit of the dystrophin glycoprotein complex (DGC), and with filamin, an actin binding protein that organizes cortical actin, to which integrins and focal adhesion complexes are anchored. The DGC is linked to the actin cytoskeleton by a dystrophin subunit and is a receptor for extracellular laminin. Thus, caveolae and caveolin-associated signalling proteins and receptors are linked via structural proteins to a dynamic filamentous actin network. Despite development of transgenic models to investigate caveolins and membrane-associated actin-linking proteins in skeletal and cardiac muscle function, only superficial understanding of this association in smooth muscle phenotype and function has emerged.Key words: caveolin, dystroglycan, filamin, mechanical plasticity, G-protein-coupled receptors.

scholarly journals ε-Sarcoglycan Replaces α-Sarcoglycan in Smooth Muscle to Form a Unique Dystrophin-Glycoprotein Complex

1999 ◽  
Vol 274 (39) ◽  
pp. 27989-27996 ◽  
Author(s):  
Volker Straub ◽  
Audrey J. Ettinger ◽  
Madeleine Durbeej ◽  
David P. Venzke ◽  
Susan Cutshall ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

scholarly journals Contraction-Induced Loss of Plasmalemmal Electrophysiological Function Is Dependent on the Dystrophin Glycoprotein Complex

2021 ◽  
Vol 12 ◽  
Author(s):  
Cory W. Baumann ◽  
Angus Lindsay ◽  
Sylvia R. Sidky ◽  
James M. Ervasti ◽  
Gordon L. Warren ◽  
...  
Keyword(s):  
M Wave ◽  
Glycoprotein Complex ◽  
Dystrophic Mouse ◽  
Dystrophin Deficiency ◽  
Torque Loss ◽  
Dystrophin Glycoprotein Complex ◽  
The Many ◽  
Dystrophin Glycoprotein ◽  
Mouse Lines

Weakness and atrophy are key features of Duchenne muscular dystrophy (DMD). Dystrophin is one of the many proteins within the dystrophin glycoprotein complex (DGC) that maintains plasmalemmal integrity and cellular homeostasis. The dystrophin-deficient mdx mouse is also predisposed to weakness, particularly when subjected to eccentric (ECC) contractions due to electrophysiological dysfunction of the plasmalemma. Here, we determined if maintenance of plasmalemmal excitability during and after a bout of ECC contractions is dependent on intact and functional DGCs rather than, solely, dystrophin expression. Wild-type (WT) and dystrophic mice (mdx, mL172H and Sgcb−/− mimicking Duchenne, Becker and Limb-girdle Type 2E muscular dystrophies, respectively) with varying levels of dystrophin and DGC functionality performed 50 maximal ECC contractions with simultaneous torque and electromyographic measurements (M-wave root-mean-square, M-wave RMS). ECC contractions caused all mouse lines to lose torque (p<0.001); however, deficits were greater in dystrophic mouse lines compared to WT mice (p<0.001). Loss of ECC torque did not correspond to a reduction in M-wave RMS in WT mice (p=0.080), while deficits in M-wave RMS exceeded 50% in all dystrophic mouse lines (p≤0.007). Moreover, reductions in ECC torque and M-wave RMS were greater in mdx mice compared to mL172H mice (p≤0.042). No differences were observed between mdx and Sgcb−/− mice (p≥0.337). Regression analysis revealed ≥98% of the variance in ECC torque loss could be explained by the variance in M-wave RMS in dystrophic mouse lines (p<0.001) but not within WT mice (R2=0.211; p=0.155). By comparing mouse lines that had varying amounts and functionality of dystrophin and other DGC proteins, we observed that (1) when all DGCs are intact, plasmalemmal action potential generation and conduction is maintained, (2) deficiency of the DGC protein β-sarcoglycan is as disruptive to plasmalemmal excitability as is dystrophin deficiency and, (3) some functionally intact DGCs are better than none. Our results highlight the significant role of the DGC plays in maintaining plasmalemmal excitability and that a collective synergism (via each DGC protein) is required for this complex to function properly during ECC contractions.

Abstract 15657: Regulation of Cardiac Regeneration by Hippo Pathway and Dystrophin Glycoprotein Complex

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Yuka Morikawa ◽  
James F Martin
Keyword(s):  
Hippo Pathway ◽  
Myocardial Damage ◽  
Cardiac Regeneration ◽  
Myocardial Cell ◽  
Damage Area ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Heart Size ◽  
The Hippo Pathway ◽  
Dystrophin Glycoprotein

Regeneration of the mammalian heart is limited in adults. In rodents, endogenous regenerative capacity exists during development and in neonate but is rapidly repressed after birth. We are elucidating the mechanisms responsible for regenerative repression and applying this knowledge to reactivate cardiac regeneration in adult hearts. We have previously shown that the Hippo pathway is responsive for regenerative repression, however, the molecular and cellular mechanism responsible remain unclear. The Hippo pathway controls heart size by repressing myocardial cell proliferation during development. By deleting Salv, a modulator of Hippo pathway, we found myocardial damage in the postnatal and adult heart was repaired anatomically and functionally. This heart repair occurred primarily through proliferation of preexisting cardiomyocyte. We observed that cardiomyocytes in border the zone protrude and fill the damage area during Hippo-mediated cardiac regeneration and thus preventing formation of fibrotic scars. The molecular analysis identified components of dystrophin glycoprotein complex (DGC) as downstream targets of Hippo pathway. The DGC anchors the cytoskeleton and extracellular matrix and is involved in cell migration. The studies using the muscular dystrophy mouse model, mdx, reveals that DGC is required for endogenous cardiac regeneration and cardiomyocyte protrusion. Taken together, we show that cardiomyocyte protrusion is an essential process for cardiac regeneration and the Hippo pathway regulates it through regulating DGC. Our studies provide insights into the mechanisms leading to repair of damaged hearts from endogenous cardiomyocytes and novel information into DGC function.

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.

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