Journal articles: 'Dystrophin Glycoprotein Complex'

1

Peter, Angela K., Jamie L. Marshall, and Rachelle H. Crosbie. "Sarcospan reduces dystrophic pathology: stabilization of the utrophin–glycoprotein complex." Journal of Cell Biology 183, no. 3 (November 3, 2008): 419–27. http://dx.doi.org/10.1083/jcb.200808027.

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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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Gumerson, Jessica D., and Daniel E. Michele. "The Dystrophin-Glycoprotein Complex in the Prevention of Muscle Damage." Journal of Biomedicine and Biotechnology 2011 (2011): 1–13. http://dx.doi.org/10.1155/2011/210797.

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Muscular dystrophies are genetically diverse but share common phenotypic features of muscle weakness, degeneration, and progressive decline in muscle function. Previous work has focused on understanding how disruptions in the dystrophin-glycoprotein complex result in muscular dystrophy, supporting a hypothesis that the muscle sarcolemma is fragile and susceptible to contraction-induced injury in multiple forms of dystrophy. Although benign in healthy muscle, contractions in dystrophic muscle may contribute to a higher degree of muscle damage which eventually overwhelms muscle regeneration capacity. While increased susceptibility of muscle to mechanical injury is thought to be an important contributor to disease pathology, it is becoming clear that not all DGC-associated diseases share this supposed hallmark feature. This paper outlines experimental support for a function of the DGC in preventing muscle damage and examines the evidence that supports novel functions for this complex in muscle that when impaired, may contribute to the pathogenesis of muscular dystrophy.

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Ohlendieck, K., and K. P. Campbell. "Dystrophin-associated proteins are greatly reduced in skeletal muscle from mdx mice." Journal of Cell Biology 115, no. 6 (December 15, 1991): 1685–94. http://dx.doi.org/10.1083/jcb.115.6.1685.

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Dystrophin, the protein product of the human Duchenne muscular dystrophy gene, exists in skeletal muscle as a large oligomeric complex that contains four glycoproteins of 156, 50, 43, and 35 kD and a protein of 59 kD. Here, we investigated the relative abundance of each of the components of the dystrophin-glycoprotein complex in skeletal muscle from normal and mdx mice, which are missing dystrophin. Immunoblot analysis using total muscle membranes from control and mdx mice of ages 1 d to 30 wk found that all of the dystrophin-associated proteins were greatly reduced (80-90%) in mdx mouse skeletal muscle. The specificity of the loss of the dystrophin-associated glycoproteins was demonstrated by the finding that the major glycoprotein composition of skeletal muscle membranes from normal and mdx mice was identical. Furthermore, skeletal muscle membranes from the dystrophic dy/dy mouse exhibited a normal density of dystrophin and dystrophin-associated proteins. Immunofluorescence microscopy confirmed the results from the immunoblot analysis and showed a drastically reduced density of dystrophin-associated proteins in mdx muscle cryosections compared with normal and dy/dy mouse muscle. Therefore, our results demonstrate that all of the dystrophin-associated proteins are significantly reduced in mdx skeletal muscle and suggest that the loss of dystrophin-associated proteins is due to the absence of dystrophin and not due to secondary effects of muscle fiber degradation.

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Culligan, Kevin, and Kay Ohlendieck. "Diversity of the Brain Dystrophin-Glycoprotein Complex." Journal of Biomedicine and Biotechnology 2, no. 1 (2002): 31–36. http://dx.doi.org/10.1155/s1110724302000347.

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Duchenne muscular dystrophy (DMD), the most common inherited neuromuscular disorder, is characterized by progressive muscle wasting and weakness. One third of Duchenne patients suffer a moderate to severe, nonprogressive form of mental retardation. Mutations in the DMD gene are thought to be responsible, with the shorter isoforms of dystrophin implicated in its molecular brain pathogenesis. It is becoming clear that region-specific variations in dystrophin isoforms delegate the composition of the dystrophin-glycoprotein complex in brain, and hence, the function of the specific membrane assembly. Here we summarize the recent advances in the understanding of brain dystrophin, dystrophin-related proteins and dystrophin-associated proteins.

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Sunada, Yoshihide, and Kevin P. Campbell. "Dystrophin-glycoprotein complex." Current Opinion in Neurology 8, no. 5 (October 1995): 379–84. http://dx.doi.org/10.1097/00019052-199510000-00010.

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6

Ohlendieck, K., J. M. Ervasti, J. B. Snook, and K. P. Campbell. "Dystrophin-glycoprotein complex is highly enriched in isolated skeletal muscle sarcolemma." Journal of Cell Biology 112, no. 1 (January 1, 1991): 135–48. http://dx.doi.org/10.1083/jcb.112.1.135.

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mAbs specific for protein components of the surface membrane of rabbit skeletal muscle have been used as markers in the isolation and characterization of skeletal muscle sarcolemma membranes. Highly purified sarcolemma membranes from rabbit skeletal muscle were isolated from a crude surface membrane preparation by wheat germ agglutination. Immunoblot analysis of subcellular fractions from skeletal muscle revealed that dystrophin and its associated glycoproteins of 156 and 50 kD are greatly enriched in purified sarcolemma vesicles. The purified sarcolemma was also enriched in novel sarcolemma markers (SL45, SL/TS230) and Na+/K(+)-ATPase, whereas t-tubule markers (alpha 1 and alpha 2 subunits of dihydropyridine receptor, TS28) and sarcoplasmic reticulum markers (Ca2(+)-ATPase, ryanodine receptor) were greatly diminished in this preparation. Analysis of isolated sarcolemma by SDS-PAGE and densitometric scanning demonstrated that dystrophin made up 2% of the total protein in the rabbit sarcolemma preparation. Therefore, our results demonstrate that although dystrophin is a minor muscle protein it is a major constituent of the sarcolemma membrane in skeletal muscle. Thus the absence of dystrophin in Duchenne muscular dystrophy may result in a major disruption of the cytoskeletal network underlying the sarcolemma in dystrophic muscle.

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Straub, Volker, Jill A. Rafael, Jeffrey S. Chamberlain, and Kevin P. Campbell. "Animal Models for Muscular Dystrophy Show Different Patterns of Sarcolemmal Disruption." Journal of Cell Biology 139, no. 2 (October 20, 1997): 375–85. http://dx.doi.org/10.1083/jcb.139.2.375.

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Genetic defects in a number of components of the dystrophin–glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Evans blue, a low molecular weight diazo dye, does not cross into skeletal muscle fibers in normal mice. In contrast, mdx mice, a dystrophin-deficient animal model for Duchenne muscular dystrophy, showed significant Evans blue accumulation in skeletal muscle fibers. We also studied Evans blue dispersion in transgenic mice bearing different dystrophin mutations, and we demonstrated that cytoskeletal and sarcolemmal attachment of dystrophin might be a necessary requirement to prevent serious fiber damage. The extent of dye incorporation in transgenic mice correlated with the phenotypic severity of similar dystrophin mutations in humans. We furthermore assessed Evans blue incorporation in skeletal muscle of the dystrophia muscularis (dy/dy) mouse and its milder allelic variant, the dy2J/dy2J mouse, animal models for congenital muscular dystrophy. Surprisingly, these mice, which have defects in the laminin α2-chain, an extracellular ligand of the DGC, showed little Evans blue accumulation in their skeletal muscles. Taken together, these results suggest that the pathogenic mechanisms in congenital muscular dystrophy are different from those in Duchenne muscular dystrophy, although the primary defects originate in two components associated with the same protein complex.

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8

Straub, Volker, and Kevin P. Campbell. "Muscular dystrophies and the dystrophin–glycoprotein complex." Current Opinion in Neurology 10, no. 2 (April 1997): 168–75. http://dx.doi.org/10.1097/00019052-199704000-00016.

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9

Lapidos, Karen A., Rahul Kakkar, and Elizabeth M. McNally. "The Dystrophin Glycoprotein Complex." Circulation Research 94, no. 8 (April 30, 2004): 1023–31. http://dx.doi.org/10.1161/01.res.0000126574.61061.25.

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10

Murphy, Sandra, Margit Zweyer, Rustam R. Mundegar, Dieter Swandulla, and Kay Ohlendieck. "Chemical crosslinking analysis of β-dystroglycan in dystrophin-deficient skeletal muscle." HRB Open Research 1 (May 30, 2018): 17. http://dx.doi.org/10.12688/hrbopenres.12846.1.

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Background: In Duchenne muscular dystrophy, primary abnormalities in the membrane cytoskeletal protein dystrophin trigger the loss of sarcolemmal linkage between the extracellular matrix component laminin-211 and the intracellular cortical actin membrane cytoskeleton. The disintegration of the dystrophin-associated glycoprotein complex renders the plasma membrane of contractile fibres more susceptible to micro-rupturing, which is associated with abnormal calcium handling and impaired cellular signalling in dystrophinopathy. Methods: The oligomerisation pattern of β-dystroglycan, an integral membrane protein belonging to the core dystrophin complex, was studied using immunoprecipitation and chemical crosslinking analysis. A homo-bifunctional and non-cleavable agent with water-soluble and amine-reactive properties was employed to study protein oligomerisation in normal versus dystrophin-deficient skeletal muscles. Crosslinker-induced protein oligomerisation was determined by a combination of gel-shift analysis and immunoblotting. Results: Although proteomics was successfully applied for the identification of dystroglycan as a key component of the dystrophin-associated glycoprotein complex in the muscle membrane fraction, mass spectrometric analysis did not efficiently recognize this relatively low-abundance protein after immunoprecipitation or chemical crosslinking. As an alternative approach, comparative immunoblotting was used to evaluate the effects of chemical crosslinking. Antibody decoration of the crosslinked microsomal protein fraction from wild type versus the mdx-4cv mouse model of dystrophinopathy revealed oligomers that contain β-dystroglycan. The protein exhibited a comparable reduction in gel electrophoretic mobility in both normal and dystrophic samples. The membrane repair proteins dysferlin and myoferlin, which are essential components of fibre regeneration and counteract the dystrophic phenotype, were also shown to exist in high-molecular mass complexes. Conclusions: The muscular dystrophy-related reduction in the concentration of β-dystroglycan, which forms in conjunction with its extracellular binding partner α-dystroglycan a critical plasmalemmal receptor for laminin-211, does not appear to alter its oligomeric status. Thus, independent of direct interactions with dystrophin, this sarcolemmal glycoprotein appears to exist in a supramolecular assembly in muscle.

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11

Iwata, Yuko, Yuki Katanosaka, Yuji Arai, Kazuo Komamura, Kunio Miyatake, and Munekazu Shigekawa. "A novel mechanism of myocyte degeneration involving the Ca2+-permeable growth factor–regulated channel." Journal of Cell Biology 161, no. 5 (June 9, 2003): 957–67. http://dx.doi.org/10.1083/jcb.200301101.

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Disruption of the dystrophin–glycoprotein complex caused by genetic defects of dystrophin or sarcoglycans results in muscular dystrophy and/or cardiomyopathy in humans and animal models. However, the key early molecular events leading to myocyte degeneration remain elusive. Here, we observed that the growth factor–regulated channel (GRC), which belongs to the transient receptor potential channel family, is elevated in the sarcolemma of skeletal and/or cardiac muscle in dystrophic human patients and animal models deficient in dystrophin or δ-sarcoglycan. However, total cell GRC does not differ markedly between normal and dystrophic muscles. Analysis of the properties of myotubes prepared from δ-sarcoglycan–deficient BIO14.6 hamsters revealed that GRC is activated in response to myocyte stretch and is responsible for enhanced Ca2+ influx and resultant cell damage as measured by creatine phosphokinase efflux. We found that cell stretch increases GRC translocation to the sarcolemma, which requires entry of external Ca2+. Consistent with these findings, cardiac-specific expression of GRC in a transgenic mouse model produced cardiomyopathy due to Ca2+ overloading, with disease expression roughly parallel to sarcolemmal GRC levels. The results suggest that GRC is a key player in the pathogenesis of myocyte degeneration caused by dystrophin–glycoprotein complex disruption.

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12

Rybakova, I. N., K. J. Amann, and J. M. Ervasti. "A new model for the interaction of dystrophin with F-actin." Journal of Cell Biology 135, no. 3 (November 1, 1996): 661–72. http://dx.doi.org/10.1083/jcb.135.3.661.

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The F-actin binding and cross-linking properties of skeletal muscle dystrophin-glycoprotein complex were examined using high and low speed cosedimentation assays, microcapillary falling ball viscometry, and electron microscopy. Dystrophin-glycoprotein complex binding to F-actin saturated near 0.042 +/- 0.005 mol/ mol, which corresponds to one dystrophin per 24 actin monomers. Dystrophin-glycoprotein complex bound to F-actin with an average apparent Kd for dystrophin of 0.5 microM. These results demonstrate that native, full-length dystrophin in the glycoprotein complex binds F-actin with some properties similar to those measured for several members of the actin cross-linking super-family of proteins. However, we failed to observe dystrophin-glycoprotein complex-induced cross-linking of F-actin by three different methods, each positively controlled with alpha-actinin. Furthermore, high speed cosedimentation analysis of dystrophin-glycoprotein complex digested with calpain revealed a novel F-actin binding site located near the middle of the dystrophin rod domain. Recombinant dystrophin fragments corresponding to the novel actin binding site and the first 246 amino acids of dystrophin both bound F-actin but with significantly lower affinity and higher capacity than was observed with purified dystrophin-glycoprotein complex. Finally, dystrophin-glycoprotein complex was observed to significantly slow the depolymerization of F-actin, Suggesting that dystrophin may lie along side an actin filament through interaction with multiple actin monomers. These data suggest that although dystrophin is most closely related to the actin cross-linking superfamily based on sequence homology, dystrophin binds F-actin in a manner more analogous to actin side-binding proteins.

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13

Hack, A. A., M. Y. Lam, L. Cordier, D. I. Shoturma, C. T. Ly, M. A. Hadhazy, M. R. Hadhazy, H. L. Sweeney, and E. M. McNally. "Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex." Journal of Cell Science 113, no. 14 (July 15, 2000): 2535–44. http://dx.doi.org/10.1242/jcs.113.14.2535.

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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.

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Teramoto, Naomi, Hidetoshi Sugihara, Keitaro Yamanouchi, Katsuyuki Nakamura, Koichi Kimura, Tomoko Okano, Takanori Shiga, et al. "Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy." Disease Models & Mechanisms 13, no. 9 (August 28, 2020): dmm044701. http://dx.doi.org/10.1242/dmm.044701.

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ABSTRACTDystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.

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Liu, Jianming, Dean J. Burkin, and Stephen J. Kaufman. "Increasing α7β1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression." American Journal of Physiology-Cell Physiology 294, no. 2 (February 2008): C627—C640. http://dx.doi.org/10.1152/ajpcell.00329.2007.

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The dystrophin-glycoprotein complex maintains the integrity of skeletal muscle by associating laminin in the extracellular matrix with the actin cytoskeleton. Several human muscular dystrophies arise from defects in the components of this complex. The α7β1-integrin also binds laminin and links the extracellular matrix with the cytoskeleton. Enhancement of α7-integrin levels alleviates pathology in mdx/utrn−/− mice, a model of Duchenne muscular dystrophy, and thus the integrin may functionally compensate for the absence of dystrophin. To test whether increasing α7-integrin levels affects transcription and cellular functions, we generated α7-integrin-inducible C2C12 cells and transgenic mice that overexpress the integrin in skeletal muscle. C2C12 myoblasts with elevated levels of integrin exhibited increased adhesion to laminin, faster proliferation when serum was limited, resistance to staurosporine-induced apoptosis, and normal differentiation. Transgenic expression of eightfold more integrin in skeletal muscle did not result in notable toxic effects in vivo. Moreover, high levels of α7-integrin in both myoblasts and in skeletal muscle did not disrupt global gene expression profiles. Thus increasing integrin levels can compensate for defects in the extracellular matrix and cytoskeleton linkage caused by compromises in the dystrophin-glycoprotein complex without triggering apparent overt negative side effects. These results support the use of integrin enhancement as a therapy for muscular dystrophy.

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Murphy, Sandra, Margit Zweyer, Rustam R. Mundegar, Dieter Swandulla, and Kay Ohlendieck. "Chemical crosslinking analysis of β-dystroglycan in dystrophin-deficient skeletal muscle." HRB Open Research 1 (September 17, 2018): 17. http://dx.doi.org/10.12688/hrbopenres.12846.2.

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Background: In Duchenne muscular dystrophy, primary abnormalities in the membrane cytoskeletal protein dystrophin trigger the loss of sarcolemmal linkage between the extracellular matrix component laminin-211 and the intracellular cortical actin membrane cytoskeleton. The disintegration of the dystrophin-associated glycoprotein complex renders the plasma membrane of contractile fibres more susceptible to micro-rupturing, which is associated with abnormal calcium handling and impaired cellular signalling in dystrophinopathy. Methods: The oligomerisation pattern of β-dystroglycan, an integral membrane protein belonging to the core dystrophin complex, was studied using immunoprecipitation and chemical crosslinking analysis. A homo-bifunctional and non-cleavable agent with water-soluble and amine-reactive properties was employed to study protein oligomerisation in normal versus dystrophin-deficient skeletal muscles. Crosslinker-induced protein oligomerisation was determined by a combination of gel-shift analysis and immunoblotting. Results: Although proteomics was successfully applied for the identification of dystroglycan as a key component of the dystrophin-associated glycoprotein complex in the muscle membrane fraction, mass spectrometric analysis did not efficiently recognize this relatively low-abundance protein after immunoprecipitation or chemical crosslinking. As an alternative approach, comparative immunoblotting was used to evaluate the effects of chemical crosslinking. Antibody decoration of the crosslinked microsomal protein fraction from wild type versus the mdx-4cv mouse model of dystrophinopathy revealed oligomers that contain β-dystroglycan. The protein exhibited a comparable reduction in gel electrophoretic mobility in both normal and dystrophic samples. The membrane repair proteins dysferlin and myoferlin, which are essential components of fibre regeneration, as well as the caveolae-associated protein cavin-1, were also shown to exist in high-molecular mass complexes. Conclusions: The muscular dystrophy-related reduction in the concentration of β-dystroglycan, which forms in conjunction with its extracellular binding partner α-dystroglycan a critical plasmalemmal receptor for laminin-211, does not appear to alter its oligomeric status. Thus, independent of direct interactions with dystrophin, this sarcolemmal glycoprotein appears to exist in a supramolecular assembly in muscle.

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Gibbs, Elizabeth M., Jackie L. McCourt, Kara M. Shin, Katherine G. Hammond, Jamie L. Marshall, and Rachelle H. Crosbie. "Loss of sarcospan exacerbates pathology in mdx mice, but does not affect utrophin amelioration of disease." Human Molecular Genetics 30, no. 3-4 (January 11, 2021): 149–59. http://dx.doi.org/10.1093/hmg/ddaa264.

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Abstract The dystrophin–glycoprotein complex (DGC) is a membrane adhesion complex that provides structural stability at the sarcolemma by linking the myocyte’s internal cytoskeleton and external extracellular matrix. In Duchenne muscular dystrophy (DMD), the absence of dystrophin leads to the loss of the DGC at the sarcolemma, resulting in sarcolemmal instability and progressive muscle damage. Utrophin (UTRN), an autosomal homolog of dystrophin, is upregulated in dystrophic muscle and partially compensates for the loss of dystrophin in muscle from patients with DMD. Here, we examine the interaction between Utr and sarcospan (SSPN), a small transmembrane protein that is a core component of both UTRN–glycoprotein complex (UGC) and DGC. We show that additional loss of SSPN causes an earlier onset of disease in dystrophin-deficient mdx mice by reducing the expression of the UGC at the sarcolemma. In order to further evaluate the role of SSPN in maintaining therapeutic levels of Utr at the sarcolemma, we tested the effect of Utr transgenic overexpression in mdx mice lacking SSPN (mdx:SSPN −/−:Utr-Tg). We found that overexpression of Utr restored SSPN to the sarcolemma in mdx muscle but that the ablation of SSPN in mdx muscle reduced Utr at the membrane. Nevertheless, Utr overexpression reduced central nucleation and improved grip strength in both lines. These findings demonstrate that high levels of Utr transgenic overexpression ameliorate the mdx phenotype independently of SSPN expression but that loss of SSPN may impair Utr-based mechanisms that rely on lower levels of Utr protein.

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Lohan, James, Kevin Culligan, and Kay Ohlendieck. "Deficiency in Cardiac Dystrophin Affects the Abundance of theα-/β-Dystroglycan Complex." Journal of Biomedicine and Biotechnology 2005, no. 1 (2005): 28–36. http://dx.doi.org/10.1155/jbb.2005.28.

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Although Duchenne muscular dystrophy is primarily categorised as a skeletal muscle disease, deficiency in the membrane cytoskeletal protein dystrophin also affects the heart. The central transsarcolemmal linker between the actin membrane cytoskeleton and the extracellular matrix is represented by the dystrophin-associated dystroglycans. Chemical cross-linking analysis revealed no significant differences in the dimeric status of theα-/β-dystroglycan subcomplex in the dystrophicmdxheart as compared to normal cardiac tissue. In analogy to skeletal muscle fibres, heart muscle also exhibited a greatly reduced abundance of both dystroglycans in dystrophin-deficient cells. Immunoblotting demonstrated that the degree of reduction inα-dystroglycan is more pronounced in maturedmdxskeletal muscle as contrasted to themdxheart. The fact that the deficiency in dystrophin triggers a similar pathobiochemical response in both types of muscle suggests that the cardiomyopathic complications observed inx-linked muscular dystrophy might be initiated by the loss of the dystrophin-associated surface glycoprotein complex.

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Ervasti, JM, and KP Campbell. "A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin." Journal of Cell Biology 122, no. 4 (August 15, 1993): 809–23. http://dx.doi.org/10.1083/jcb.122.4.809.

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The dystrophin-glycoprotein complex was tested for interaction with several components of the extracellular matrix as well as actin. The 156-kD dystrophin-associated glycoprotein (156-kD dystroglycan) specifically bound laminin in a calcium-dependent manner and was inhibited by NaCl (IC50 = 250 mM) but was not affected by 1,000-fold (wt/wt) excesses of lactose, IKVAV, or YIGSR peptides. Laminin binding was inhibited by heparin (IC50 = 100 micrograms/ml), suggesting that one of the heparin-binding domains of laminin is involved in binding dystroglycan while negatively charged oligosaccharide moieties on dystroglycan were found to be necessary for its laminin-binding activity. No interaction between any component of the dystrophin-glycoprotein complex and fibronectin, collagen I, collagen IV, entactin, or heparan sulfate proteoglycan was detected by 125I-protein overlay and/or extracellular matrix protein-Sepharose precipitation. In addition, laminin-Sepharose quantitatively precipitated purified dystrophin-glycoprotein complex, demonstrating that the laminin-binding site is accessible when dystroglycan is associated with the complex. Dystroglycan of nonmuscle tissues also bound laminin. However, the other proteins of the striated muscle dystrophin-glycoprotein complex appear to be absent, antigenically dissimilar or less tightly associated with dystroglycan in nonmuscle tissues. Finally, we show that the dystrophin-glycoprotein complex cosediments with F-actin but does not bind calcium or calmodulin. Our results support a role for the striated muscle dystrophin-glycoprotein complex in linking the actin-based cytoskeleton with the extracellular matrix. Furthermore, our results suggest that dystrophin and dystroglycan may play substantially different functional roles in nonmuscle tissues.

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Madhavan, Raghavan, and Harry W. Jarrett. "Interactions between dystrophin glycoprotein complex proteins." Biochemistry 34, no. 38 (September 26, 1995): 12204–9. http://dx.doi.org/10.1021/bi00038a014.

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Yoshida, Mikiharu, and Eijiro Ozawa. "Glycoprotein Complex Anchoring Dystrophin to Sarcolemma1." Journal of Biochemistry 108, no. 5 (November 1990): 748–52. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a123276.

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Garbincius, Joanne F., and Daniel E. Michele. "Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling." Proceedings of the National Academy of Sciences 112, no. 44 (October 19, 2015): 13663–68. http://dx.doi.org/10.1073/pnas.1512991112.

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Patients deficient in dystrophin, a protein that links the cytoskeleton to the extracellular matrix via the dystrophin–glycoprotein complex (DGC), exhibit muscular dystrophy, cardiomyopathy, and impaired muscle nitric oxide (NO) production. We used live-cell NO imaging and in vitro cyclic stretch of isolated adult mouse cardiomyocytes as a model system to investigate if and how the DGC directly regulates the mechanical activation of muscle NO signaling. Acute activation of NO synthesis by mechanical stretch was impaired in dystrophin-deficient mdx cardiomyocytes, accompanied by loss of stretch-induced neuronal NO synthase (nNOS) S1412 phosphorylation. Intriguingly, stretch induced the acute activation of AMP-activated protein kinase (AMPK) in normal cardiomyocytes but not in mdx cardiomyocytes, and specific inhibition of AMPK was sufficient to attenuate mechanoactivation of NO production. Therefore, we tested whether direct pharmacologic activation of AMPK could bypass defective mechanical signaling to restore nNOS activity in dystrophin-deficient cardiomyocytes. Indeed, activation of AMPK with 5-aminoimidazole-4-carboxamide riboside or salicylate increased nNOS S1412 phosphorylation and was sufficient to enhance NO production in mdx cardiomyocytes. We conclude that the DGC promotes the mechanical activation of cardiac nNOS by acting as a mechanosensor to regulate AMPK activity, and that pharmacologic AMPK activation may be a suitable therapeutic strategy for restoring nNOS activity in dystrophin-deficient hearts and muscle.

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Winder, S. J., L. Hemmings, S. K. Maciver, S. J. Bolton, J. M. Tinsley, K. E. Davies, D. R. Critchley, and J. Kendrick-Jones. "Utrophin actin binding domain: analysis of actin binding and cellular targeting." Journal of Cell Science 108, no. 1 (January 1, 1995): 63–71. http://dx.doi.org/10.1242/jcs.108.1.63.

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Utrophin, or dystrophin-related protein, is an autosomal homologue of dystrophin. The protein is apparently ubiquitously expressed and in muscle tissues the expression is developmentally regulated. Since utrophin has a similar domain structure to dystrophin it has been suggested that it could substitute for dystrophin in dystrophic muscle. Like dystrophin, utrophin has been shown to be associated with a membrane-bound glycoprotein complex. Here we demonstrate that expressed regions of the predicted actin binding domain in the NH2 terminus of utrophin are able to bind to F-actin in vitro, but do not interact with G-actin. The utrophin actin binding domain was also able to associate with actin-containing structures, stress fibres and focal contacts, when microinjected into chick embryo fibroblasts. The expressed NH2-terminal 261 amino acid domain of utrophin has an affinity for skeletal F-action (Kd 19 +/- 2.8 microM), midway between that of the corresponding domains of alpha-actinin (Kd 4 microM) and dystrophin (Kd 44 microM). Moreover, this utrophin domain binds to non-muscle actin with a approximately 4-fold higher affinity than to skeletal muscle actin. These data (together with those of Matsumura et al. (1992) Nature, 360, 588–591) demonstrate for the first time that utrophin is capable of performing a functionally equivalent role to that of dystrophin. The NH2 terminus of utrophin binds to actin and the COOH terminus binds to the membrane associated glycoprotein complex, thus in non-muscle and developing muscle utrophin performs the same predicted ‘spacer’ or ‘shock absorber’ role as dystrophin in mature muscle tissues. These data suggest that utrophin could replace dystrophin functionally in dystrophic muscle.

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Law, D. J., D. L. Allen, and J. G. Tidball. "Talin, vinculin and DRP (utrophin) concentrations are increased at mdx myotendinous junctions following onset of necrosis." Journal of Cell Science 107, no. 6 (June 1, 1994): 1477–83. http://dx.doi.org/10.1242/jcs.107.6.1477.

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Duchenne muscular dystrophy (DMD) and the myopathy seen in the mdx mouse both result from absence of the protein dystrophin. Structural similarities between dystrophin and other cytoskeletal proteins, its enrichment at myotendinous junctions, and its indirect association with laminin mediated by a transmembrane glycoprotein complex suggest that one of dystrophin's functions in normal muscle is to form one of the links between the actin cytoskeleton and the extracellular matrix. Unlike Duchenne muscular dystrophy patients, mdx mice suffer only transient muscle necrosis, and are able to regenerate damaged muscle tissue. The present study tests the hypothesis that mdx mice partially compensate for dystrophin's absence by upregulating one or more dystrophin-independent mechanisms of cytoskeleton-membrane association. Quantitative analysis of immunoblots of adult mdx muscle samples showed an increase of approximately 200% for vinculin and talin, cytoskeletal proteins that mediate thin filament-membrane interactions at myotendinous junctions. Blots also showed an increase (143%) in the dystrophin-related protein called utrophin, another myotendinous junction constituent, which may be able to substitute for dystrophin directly. Muscle samples from 2-week-old animals, a period immediately preceding the onset of muscle necrosis, showed no significant differences in protein concentration between mdx and controls. Quantitative analyses of confocal images of myotendinous junctions from mdx and control muscles show significantly higher concentrations of talin and vinculin at the myotendinous junctions of mdx muscle. These findings indicate that mdx mice may compensate in part for the absence of dystrophin by increased expression of other molecules that subsume dystrophin's mechanical function.

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Jakubiec-Puka, Anna, Donatella Biral, Kazimierz Krawczyk, and Romeo Betto. "Ultrastructure of diaphragm from dystrophic alpha-sarcoglycan-null mice." Acta Biochimica Polonica 52, no. 2 (June 30, 2005): 453–60. http://dx.doi.org/10.18388/abp.2005_3459.

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alpha-Sarcoglycan is a 50 kDa single-pass transmembrane glycoprotein exclusively expressed in striated muscle that, together with beta-, gamma-, and delta-sarcoglycan, forms a sub-complex at the muscle fibre cell membrane. The sarcoglycans are components of the dystrophin-associated glycoprotein (DAG) complex which forms a mechanical link between the intracellular cytoskeleton and extracellular matrix. The DAG complex function is to protect the muscle membrane from the stress of contractile activity and as a structure for the docking of signalling proteins. Genetic defects of DAG components cause muscular dystrophies. A lack or defects of alpha-sarcoglycan causes the severe type 2D limb girdle muscular dystrophy. alpha-Sarcoglycan-null (Sgca-null) mice develop progressive muscular dystrophy similar to the human disorder. This animal model was used in the present work for an ultrastructural study of diaphragm muscle. Diaphragm from Sgca-null mouse presents a clear dystrophic phenotype, with necrosis, regeneration, fibre hypertrophy and splitting, excess of collagen and fatty infiltration. Some abnormalities were also observed, such as centrally located nuclei of abnormal shape, fibres containing inclusion bodies within the contractile structure, and fibres with electron-dense material dispersed over almost the entire cell. Additionally, unusual interstitial cells of uncertain identity were detected within muscle fibres. The abnormal ultrastructure of the diaphragm from Sgca-null mice is discussed.

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Worton, R. "ENHANCED PERSPECTIVE: Muscular Dystrophies--Diseases of the Dystrophin-Glycoprotein Complex." Science 270, no. 5237 (November 3, 1995): 755. http://dx.doi.org/10.1126/science.270.5237.755.

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Mirabella, M., G. Galluzzi, G. Manfredi, E. Bertini, E. Ricci, R. De Leo, P. Tonali, and S. Servidei. "Giant dystrophin deletion associated with congenital cataract and mild muscular dystrophy." Neurology 51, no. 2 (August 1998): 592–95. http://dx.doi.org/10.1212/wnl.51.2.592.

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We report a patient with a large intragenic dystrophin deletion of exons 17-51 inclusive associated with congenital cataract and mild Becker muscular dystrophy. The cataract was similar to the congenital cataract described in the mdx mouse. The loss of 68% of the rod domain including hinge 2 and 3 regions did not adversely affect the correct localization of the dystrophin and the association with the dystrophin-associated glycoprotein complex. This observation may have implications for minigenes suitable for gene therapy.

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Thompson, Terri G., Yiu-Mo Chan, Andrew A. Hack, Melissa Brosius, Michael Rajala, Hart G. W. Lidov, Elizabeth M. McNally, Simon Watkins, and Louis M. Kunkel. "Filamin 2 (FLN2): A Muscle-specific Sarcoglycan Interacting Protein." Journal of Cell Biology 148, no. 1 (January 10, 2000): 115–26. http://dx.doi.org/10.1083/jcb.148.1.115.

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Mutations in genes encoding for the sarcoglycans, a subset of proteins within the dystrophin–glycoprotein complex, produce a limb-girdle muscular dystrophy phenotype; however, the precise role of this group of proteins in the skeletal muscle is not known. To understand the role of the sarcoglycan complex, we looked for sarcoglycan interacting proteins with the hope of finding novel members of the dystrophin–glycoprotein complex. Using the yeast two-hybrid method, we have identified a skeletal muscle-specific form of filamin, which we term filamin 2 (FLN2), as a γ- and δ-sarcoglycan interacting protein. In addition, we demonstrate that FLN2 protein localization in limb-girdle muscular dystrophy and Duchenne muscular dystrophy patients and mice is altered when compared with unaffected individuals. Previous studies of filamin family members have determined that these proteins are involved in actin reorganization and signal transduction cascades associated with cell migration, adhesion, differentiation, force transduction, and survival. Specifically, filamin proteins have been found essential in maintaining membrane integrity during force application. The finding that FLN2 interacts with the sarcoglycans introduces new implications for the pathogenesis of muscular dystrophy.

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Assereto, Stefania, Silvia Stringara, Federica Sotgia, Gloria Bonuccelli, Aldobrando Broccolini, Marina Pedemonte, Monica Traverso, et al. "Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment." American Journal of Physiology-Cell Physiology 290, no. 2 (February 2006): C577—C582. http://dx.doi.org/10.1152/ajpcell.00434.2005.

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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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Dunckley, M. G., K. E. Wells, T. A. Piper, D. J. Wells, and G. Dickson. "Independent localization of dystrophin N- and C-terminal regions to the sarcolemma of mdx mouse myofibres in vivo." Journal of Cell Science 107, no. 6 (June 1, 1994): 1469–75. http://dx.doi.org/10.1242/jcs.107.6.1469.

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Dystrophin has been proposed to associate with the skeletal muscle membrane by way of a glycoprotein complex that interacts with its C-terminal domains. Transfection of mdx mouse myotubes in culture or myofibres in vivo with recombinant genes encoding human dystrophin deletion mutants shows, however, that not only the C terminus of dystrophin but also its N-terminal actin-binding domain can locate independently to the muscle sarcolemma. This observation suggests that lack of sarcolemma-associated dystrophin in Duchenne muscular dystrophy (DMD) muscle may result from enhanced degradation of truncated mutation products rather than their inability per se to associate with the sarcolemma.

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CULLIGAN, KEVIN, and KAY OHLENDIECK. "Characterization of the brain dystrophin-glycoprotein complex." Biochemical Society Transactions 28, no. 1 (February 1, 2000): A31. http://dx.doi.org/10.1042/bst028a031c.

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Bhat, Hina F., Saima S. Mir, Khalid B. Dar, Zuhaib F. Bhat, Riaz A. Shah, and Nazir A. Ganai. "ABC of multifaceted dystrophin glycoprotein complex (DGC)." Journal of Cellular Physiology 233, no. 7 (June 22, 2017): 5142–59. http://dx.doi.org/10.1002/jcp.25982.

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Ervasti, James M., and Kevin P. Campbell. "Membrane organization of the dystrophin-glycoprotein complex." Cell 66, no. 6 (September 1991): 1121–31. http://dx.doi.org/10.1016/0092-8674(91)90035-w.

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Campbell, Matthew D., Marc Witcher, Anoop Gopal, and Daniel E. Michele. "Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability." American Journal of Physiology-Heart and Circulatory Physiology 310, no. 9 (May 1, 2016): H1140—H1150. http://dx.doi.org/10.1152/ajpheart.00521.2015.

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Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/dilated-cardiomyopathy-delta-sarcoglycan-mutations-cause-cardiomyocyte-membrane-instability/ .

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Lu, Q. L., G. E. Morris, S. D. Wilton, T. Ly, O. V. Artem'yeva, P. Strong, and T. A. Partridge. "Massive Idiosyncratic Exon Skipping Corrects the Nonsense Mutation in Dystrophic Mouse Muscle and Produces Functional Revertant Fibers by Clonal Expansion." Journal of Cell Biology 148, no. 5 (March 6, 2000): 985–96. http://dx.doi.org/10.1083/jcb.148.5.985.

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Conventionally, nonsense mutations within a gene preclude synthesis of a full-length functional protein. Obviation of such a blockage is seen in the mdx mouse, where despite a nonsense mutation in exon 23 of the dystrophin gene, occasional so-called revertant muscle fibers are seen to contain near-normal levels of its protein product. Here, we show that reversion of dystrophin expression in mdx mice muscle involves unprecedented massive loss of up to 30 exons. We detected several alternatively processed transcripts that could account for some of the revertant dystrophins and could not detect genomic deletion from the region commonly skipped in revertant dystrophin. This, together with exon skipping in two noncontiguous regions, favors aberrant splicing as the mechanism for the restoration of dystrophin, but is hard to reconcile with the clonal idiosyncrasy of revertant dystrophins. Revertant dystrophins retain functional domains and mediate plasmalemmal assembly of the dystrophin-associated glycoprotein complex. Physiological function of revertant fibers is demonstrated by the clonal growth of revertant clusters with age, suggesting that revertant dystrophin could be used as a guide to the construction of dystrophin expression vectors for individual gene therapy. The dystrophin gene in the mdx mouse provides a favored system for study of exon skipping associated with nonsense mutations.

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Fabbrizio, E., U. Nudel, G. Hugon, A. Robert, F. Pons, and D. Mornet. "Characterization and localization of a 77 kDa protein related to the dystrophin gene family." Biochemical Journal 299, no. 2 (April 15, 1994): 359–65. http://dx.doi.org/10.1042/bj2990359.

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The Duchenne muscular dystrophy gene gives rise to transcripts of several lengths. These mRNAs differ in their coding content and tissue distribution. The 14 kb mRNA encodes dystrophin, a 427 kDa protein found in muscle and brain, and the short transcripts described encode DP71, a 77 kDa protein found in various organs. These short transcripts have many features common to the deduced primary structure of dystrophin, especially in the cysteine-rich specific C-terminal domains. The dystrophin C-terminal domain could be involved in membrane anchorage via the glycoprotein complex, but such a functional role for these short transcript products has yet to be demonstrated. Here we report the first isolation of a short transcript product from saponin-solubilized cardiac muscle membranes using alkaline buffer and affinity chromatography procedures. This molecule was found to be glycosylated and could be easily dissociated from cardiac muscle and other non-muscle tissues such as brain and liver. DP71-specific monoclonal antibody helped to identify this molecule as being related to the dystrophin gene family. Immunofluorescence analysis of bovine or chicken cardiac muscle showed a periodic distribution of DP71 in transverse T tubules and this protein was co-localized with the dystrophin glycoprotein complex in the Z-disk area.

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Burkin, Dean J., Gregory Q. Wallace, Kimberly J. Nicol, David J. Kaufman, and Stephen J. Kaufman. "Enhanced Expression of the α7β1 Integrin Reduces Muscular Dystrophy and Restores Viability in Dystrophic Mice." Journal of Cell Biology 152, no. 6 (March 19, 2001): 1207–18. http://dx.doi.org/10.1083/jcb.152.6.1207.

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Muscle fibers attach to laminin in the basal lamina using two distinct mechanisms: the dystrophin glycoprotein complex and the α7β1 integrin. Defects in these linkage systems result in Duchenne muscular dystrophy (DMD), α2 laminin congenital muscular dystrophy, sarcoglycan-related muscular dystrophy, and α7 integrin congenital muscular dystrophy. Therefore, the molecular continuity between the extracellular matrix and cell cytoskeleton is essential for the structural and functional integrity of skeletal muscle. To test whether the α7β1 integrin can compensate for the absence of dystrophin, we expressed the rat α7 chain in mdx/utr−/− mice that lack both dystrophin and utrophin. These mice develop a severe muscular dystrophy highly akin to that in DMD, and they also die prematurely. Using the muscle creatine kinase promoter, expression of the α7BX2 integrin chain was increased 2.0–2.3-fold in mdx/utr−/− mice. Concomitant with the increase in the α7 chain, its heterodimeric partner, β1D, was also increased in the transgenic animals. Transgenic expression of the α7BX2 chain in the mdx/utr−/− mice extended their longevity by threefold, reduced kyphosis and the development of muscle disease, and maintained mobility and the structure of the neuromuscular junction. Thus, bolstering α7β1 integrin–mediated association of muscle cells with the extracellular matrix alleviates many of the symptoms of disease observed in mdx/utr−/− mice and compensates for the absence of the dystrophin- and utrophin-mediated linkage systems. This suggests that enhanced expression of the α7β1 integrin may provide a novel approach to treat DMD and other muscle diseases that arise due to defects in the dystrophin glycoprotein complex. A video that contrasts kyphosis, gait, joint contractures, and mobility in mdx/utr−/− and α7BX2-mdx/utr−/−mice can be accessed at http://www.jcb.org/cgi/content/full/152/6/1207.

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Barton, Elisabeth R. "Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle." American Journal of Physiology-Cell Physiology 290, no. 2 (February 2006): C411—C419. http://dx.doi.org/10.1152/ajpcell.00192.2005.

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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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Claudepierre, T., C. Dalloz, D. Mornet, K. Matsumura, J. Sahel, and A. Rendon. "Characterization of the intermolecular associations of the dystrophin-associated glycoprotein complex in retinal Muller glial cells." Journal of Cell Science 113, no. 19 (October 1, 2000): 3409–17. http://dx.doi.org/10.1242/jcs.113.19.3409.

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The abnormal retinal neurotransmission observed in Duchenne muscular dystrophy patients has been attributed to altered expression of C-terminal products of the dystrophin gene in this tissue. Muller glial cells from rat retina express dystrophin protein Dp71, utrophin and the members of the dystrophin-associated glycoprotein complex (DGC), namely beta-dystroglycan, delta- and gamma-sarcoglycans and alpha1-syntrophin. The DGC could function in muscle as a link between the cystoskeleton and the extracellular matrix, as well as a signaling complex. However, other than in muscle the composition and intermolecular associations among members of the DGC are still unknown. Here we demonstrate that Dp71 and/or utrophin from rat retinal Muller glial cells form a complex with beta-dystroglycan, delta-sarcoglycan and alpha1-syntrophin. We also show that beta-dystroglycan is associated with alpha-dystrobrevin-1 and PSD-93 and that anti-PSD antibodies coimmunoprecipitated alpha-syntrophin with PSD-93. By overlay experiments we also found that Dp71and/or utrophin and alpha-dystroglycan from Muller cells could bind to actin and laminin, respectively. These results indicate that the DGC could have both structural and signaling functions in retina. On the basis of our accumulated evidence, we propose a hypothetical model for the molecular organization of the dystrophin-associated glycoprotein complex in retinal Muller glial cells, which would be helpful for understanding its function in the central nervous system.

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Chockalingam, Priya Sethu, Rushina Cholera, Shilpa A. Oak, Yi Zheng, Harry W. Jarrett, and Donald B. Thomason. "Dystrophin-glycoprotein complex and Ras and Rho GTPase signaling are altered in muscle atrophy." American Journal of Physiology-Cell Physiology 283, no. 2 (August 1, 2002): C500—C511. http://dx.doi.org/10.1152/ajpcell.00529.2001.

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The dystrophin-glycoprotein complex (DGC) is a sarcolemmal complex whose defects cause muscular dystrophies. The normal function of this complex is not clear. We have proposed that this is a signal transduction complex, signaling normal interactions with matrix laminin, and that the response is normal growth and homeostasis. If so, the complex and its signaling should be altered in other physiological states such as atrophy. The amount of some of the DGC proteins, including dystrophin, β-dystroglycan, and α-sarcoglycan, is reduced significantly in rat skeletal muscle atrophy induced by tenotomy. Furthermore, H-Ras, RhoA, and Cdc42 decrease in expression levels and activities in muscle atrophy. When the small GTPases were assayed after laminin or β-dystroglycan depletion, H-Ras, Rac1, and Cdc42 activities were reduced, suggesting a physical linkage between the DGC and the GTPases. Dominant-negative Cdc42, introduced with a retroviral vector, resulted in fibers that appeared atrophic. These data support a putative role for the DGC in transduction of mechanical signals in muscle.

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Hakim, Chady H., Dean J. Burkin, and Dongsheng Duan. "Alpha 7 integrin preserves the function of the extensor digitorum longus muscle in dystrophin-null mice." Journal of Applied Physiology 115, no. 9 (November 1, 2013): 1388–92. http://dx.doi.org/10.1152/japplphysiol.00602.2013.

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The dystrophin-associated glycoprotein complex (DGC) and the α7β1-integrin complex are two independent protein complexes that link the extracellular matrix with the cytoskeleton in muscle cells. These associations stabilize the sarcolemma during force transmission. Loss of either one of these complexes leads to muscular dystrophy. Dystrophin is a major component of the DGC. Its absence results in Duchenne muscular dystrophy (DMD). Because α7-integrin overexpression has been shown to ameliorate muscle histopathology in mouse models of DMD, we hypothesize that the α7β1-integrin complex can help preserve muscle function. To test this hypothesis, we evaluated muscle force, elasticity, and the viscous property of the extensor digitorum longus muscle in 19-day-old normal BL6, dystrophin-null mdx4cv, α7-integrin-null, and dystrophin/α7-integrin double knockout mice. While nominal changes were found in single knockout mice, contractility and passive properties were significantly compromised in α7-integrin double knockout mice. Our results suggest that DGC and α7β1-integrin complexes may compensate each other to maintain normal skeletal muscle function. α7β1-Integrin upregulation may hold promise to treat not only histological, but also physiological, defects in DMD.

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Kikuchi, Tateki. "Caveolin-3: A Causative Process of Chicken Muscular Dystrophy." Biomolecules 10, no. 9 (August 20, 2020): 1206. http://dx.doi.org/10.3390/biom10091206.

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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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Ervasti, James M., Kay Ohlendieck, Steven D. Kahl, Mitchell G. Gaver, and Kevin P. Campbell. "Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle." Nature 345, no. 6273 (May 1990): 315–19. http://dx.doi.org/10.1038/345315a0.

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Holland, Ashling, Steven Carberry, and Kay Ohlendieck. "Proteomics of the Dystrophin-glycoprotein Complex and Dystrophinopathy." Current Protein & Peptide Science 14, no. 8 (December 31, 2013): 680–97. http://dx.doi.org/10.2174/13892037113146660083.

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Allikian, Michael J., and Elizabeth M. McNally. "Processing and Assembly of the Dystrophin Glycoprotein Complex." Traffic 8, no. 3 (November 28, 2006): 177–83. http://dx.doi.org/10.1111/j.1600-0854.2006.00519.x.

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Waite, Adrian, Caroline L. Tinsley, Matthew Locke, and Derek J. Blake. "The neurobiology of the dystrophin-associated glycoprotein complex." Annals of Medicine 41, no. 5 (January 2009): 344–59. http://dx.doi.org/10.1080/07853890802668522.

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Dowling, Paul, Stephen Gargan, Sandra Murphy, Margit Zweyer, Hemmen Sabir, Dieter Swandulla, and Kay Ohlendieck. "The Dystrophin Node as Integrator of Cytoskeletal Organization, Lateral Force Transmission, Fiber Stability and Cellular Signaling in Skeletal Muscle." Proteomes 9, no. 1 (February 2, 2021): 9. http://dx.doi.org/10.3390/proteomes9010009.

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The systematic bioanalytical characterization of the protein product of the DMD gene, which is defective in the pediatric disorder Duchenne muscular dystrophy, led to the discovery of the membrane cytoskeletal protein dystrophin. Its full-length muscle isoform Dp427-M is tightly linked to a sarcolemma-associated complex consisting of dystroglycans, sarcoglyans, sarcospan, dystrobrevins and syntrophins. Besides these core members of the dystrophin–glycoprotein complex, the wider dystrophin-associated network includes key proteins belonging to the intracellular cytoskeleton and microtubular assembly, the basal lamina and extracellular matrix, various plasma membrane proteins and cytosolic components. Here, we review the central role of the dystrophin complex as a master node in muscle fibers that integrates cytoskeletal organization and cellular signaling at the muscle periphery, as well as providing sarcolemmal stabilization and contractile force transmission to the extracellular region. The combination of optimized tissue extraction, subcellular fractionation, advanced protein co-purification strategies, immunoprecipitation, liquid chromatography and two-dimensional gel electrophoresis with modern mass spectrometry-based proteomics has confirmed the composition of the core dystrophin complex at the sarcolemma membrane. Importantly, these biochemical and mass spectrometric surveys have identified additional members of the wider dystrophin network including biglycan, cavin, synemin, desmoglein, tubulin, plakoglobin, cytokeratin and a variety of signaling proteins and ion channels.

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Matsumura, Kiichiro, and Kevin P. Campbell. "Dystrophin-glycoprotein complex: Its role in the molecular pathogenesis of muscular dystrophies." Muscle & Nerve 17, no. 1 (January 1994): 2–15. http://dx.doi.org/10.1002/mus.880170103.

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CHEN, Yun-Ju, Heather J. SPENCE, Jacqueline M. CAMERON, Thomas JESS, Jane L. ILSLEY, and Steven J. WINDER. "Direct interaction of β-dystroglycan with F-actin." Biochemical Journal 375, no. 2 (October 15, 2003): 329–37. http://dx.doi.org/10.1042/bj20030808.

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Dystroglycans are essential transmembrane adhesion receptors for laminin. α-Dystroglycan is a highly glycosylated extracellular protein that interacts with laminin in the extracellular matrix and the transmembrane region of β-dystroglycan. β-Dystroglycan, via its cytoplasmic tail, interacts with dystrophin and utrophin and also with the actin cytoskeleton. As a part of the dystrophin–glycoprotein complex of muscles, dystroglycan is also important in maintaining sarcolemmal integrity. Mutations in dystrophin that lead to Duchenne muscular dystrophy also lead to a loss of dystroglycan from the sarcolemma, and chimaeric mice lacking muscle dystroglycan exhibit a severe muscular dystrophy phenotype. Using yeast two-hybrid analysis and biochemical and cell biological studies, we show, in the present study, that the cytoplasmic tail of β-dystroglycan interacts directly with F-actin and, furthermore, that it bundles actin filaments and induces an aberrant actin phenotype when overexpressed in cells.

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Rivier, F., A. Robert, Y. Chaix, M. B. Delisle, A. Bonet-Kerrache, B. Echenne, and D. Mornet. "Dystrophin associated glycoprotein complex in a particular case of Becker muscular dystrophy." Neuromuscular Disorders 7, no. 6-7 (September 1997): 435. http://dx.doi.org/10.1016/s0960-8966(97)87195-7.

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Journal articles on the topic 'Dystrophin Glycoprotein Complex'

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