P3.08 Induction of dystrophin in DMD patients by antisense oligonucleotide AVI-4658 restores the dystrophin glycoprotein complex

2010 ◽  
Vol 20 (9-10) ◽  
pp. 643
Author(s):  
S. Cirak ◽  
L. Feng ◽  
S. Torelli ◽  
V. Arechavala-Gomeza ◽  
M. Kinali ◽  
...  
Keyword(s):  
Antisense Oligonucleotide ◽  
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.

scholarly journals Processing and Assembly of the Dystrophin Glycoprotein Complex

Traffic ◽  
2006 ◽  
Vol 8 (3) ◽  
pp. 177-183 ◽  
Author(s):  
Michael J. Allikian ◽  
Elizabeth M. McNally
Keyword(s):  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

scholarly journals The Dystrophin Glycoprotein Complex Regulates the Epigenetic Activation of Muscle Stem Cell Commitment

2018 ◽  
Vol 22 (5) ◽  
pp. 755-768.e6 ◽  
Author(s):  
Natasha C. Chang ◽  
Marie-Claude Sincennes ◽  
Fabien P. Chevalier ◽  
Caroline E. Brun ◽  
Melanie Lacaria ◽  
...  
Keyword(s):  
Stem Cell ◽  
Muscle Stem Cell ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Cell Commitment ◽  
Dystrophin Glycoprotein

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 A signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yara Eid Mutlak ◽  
Dina Aweida ◽  
Alexandra Volodin ◽  
Bar Ayalon ◽  
Nitsan Dahan ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Muscle Size ◽  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein

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.

scholarly journals Bortezomib (PS-341) Treatment Decreases Inflammation and Partially Rescues the Expression of the Dystrophin-Glycoprotein Complex in GRMD Dogs

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e61367 ◽  
Author(s):  
Karla P. C. Araujo ◽  
Gloria Bonuccelli ◽  
Caio N. Duarte ◽  
Thais P. Gaiad ◽  
Dayson F. Moreira ◽  
...  
Keyword(s):  
Glycoprotein Complex ◽  
Dystrophin Glycoprotein Complex ◽  
Dystrophin Glycoprotein
Sign in / Sign up

Export Citation Format

Share Document