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Paul T Martin

Publications and source records attributed to Paul T Martin.

At least 19 recordsLinked to original sources
PubMed2006

Benefit of millisecond waveform durations for patients with high defibrillation thresholds.

BACKGROUND: Patients with a high defibrillation threshold (DFT) present an atypical but vexing problem with regard to implantable cardioverter-defibrillator (ICD) therapy. Their implant procedures are lengthy and involve more risk of complications. These patients often sustain a reduced safety margin that may compromise their survival. OBJECTIVES: The purpose of this study was to evaluate the use of fixed millisecond duration model-optimized biphasic waveforms compared with conventional tilt-based waveforms in patients having a high DFT. METHODS: We compared a 65%/65% tilt biphasic waveform to a millisecond duration biphasic waveform based on the biphasic burping theory using a 90-microF shock capacitor. RESULTS: Fifty-four patients were evaluated. Mean DFT with tilt was reduced from 11.0 +/- 5.5 J to 8.8 +/- 4.1 J, for a mean reduction of 20% (P < .0001). For the 13 patients with tilt-based DFTs > or = 15 J, DFT was reduced from 18.7 +/- 4.1 J to 13.4 +/- 3.5 J, for a mean DFT reduction of 28% (P = .009). The population peak DFT was reduced from 29.0 J to 17.5 J, for a 41% reduction (P = .03). CONCLUSION: Use of simple millisecond biphasic waveforms instead of conventional tilt-based waveforms can lead to substantial reductions in DFT, especially in patients with high DFT.

Adult↗
PubMed2006

Mechanisms of disease: congenital muscular dystrophies-glycosylation takes center stage.

Recent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of alpha-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.

Animals↗
PubMed2005

The dystroglycanopathies: the new disorders of O-linked glycosylation.

It has become clear in the past half decade that a number of forms of congenital muscular dystrophy are in fact congenital disorders of glycosylation. Genes for Walker Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, congenital muscular dystrophy 1C and 1D, and limb girdle muscular dystrophy 21 have been identified, and gene mutations resulting in these diseases all cause the underglycosylation of alpha dystroglycan with O-linked carbohydrates. Unlike congenital disorders of glycosylation involving the N-linked pathway, these O-linked disorders possess distinctive muscle, eye, and brain phenotypes. Studies using mice and patient tissues strongly suggest that underglycosylation of dystroglycan inhibits the binding extracellular matrix proteins, effectively divorcing this important cell adhesion molecule from its extracellular environment. Moreover, defects in dystroglycan alone can account for most, if not all, cellular pathology. Thus, these disorders are now collectively referred to as dystroglycanopathies.

Dystroglycans↗
PubMed2004

Muscular dystrophy with truncated dystrophin in a family of Japanese Spitz dogs.

Muscular dystrophy was diagnosed in seven male Japanese Spitz dogs with clinical signs of slowly progressive exercise intolerance, generalized weakness, myalgia, difficulty chewing and dysphagia. Serum creatine kinase (CK) concentrations were markedly elevated. Histopathology showed degeneration and regeneration of muscle, consistent with a dystrophic phenotype. Immunohistochemical staining for dystrophin and related proteins showed no staining with a monoclonal antibody against the rod domain of dystrophin but near-normal staining with an antibody against the C terminus. Immunoblot analysis in two affected dogs showed a truncated dystrophin protein of approximately 70-80 kDa. The severity of disease showed that this fragment was not large enough to protect from the dystrophic process.

Animals↗
PubMed2004

Transgenic overexpression of dystroglycan does not inhibit muscular dystrophy in mdx mice.

Recently, there have been a number of studies demonstrating that overexpression of molecules in skeletal muscle can inhibit or ameliorate aspects of muscular dystrophy in the mdx mouse, a model for Duchenne muscular dystrophy. Several such studies involve molecules that increase the expression of dystroglycan, an important component of the dystrophin-glycoprotein complex. To test whether dystroglycan itself inhibits muscular dystrophy in mdx mice, we created dystroglycan transgenic mdx mice (DG/mdx). The alpha and beta chains of dystroglycan were highly overexpressed along the sarcolemmal membrane in most DG/mdx muscles. Increased dystroglycan expression, however, did not correlate with increased expression of utrophin or sarcoglycans, but rather caused their decreased expression. In addition, the percentage of centrally located myofiber nuclei and the level of serum creatine kinase activity were not decreased in DG/mdx mice relative to mdx animals. Therefore, dystroglycan overexpression does not cause the concomitant overexpression of a utrophin-glycoprotein complex in mdx muscles and has no effect on the development of muscle pathology associated with muscular dystrophy.

Animals↗
PubMed2003

Dystroglycan glycosylation and its role in matrix binding in skeletal muscle.

Dystroglycan is an essential component of the dystrophin-glycoprotein complex. Three glycan sequencing studies have identified O-linked mannose chains, including NeuAcalpha 2,3Galbeta 1,4GlcNAcbeta 1,2Manalpha-O, on alpha dystroglycan. Chemical deglycosylation of alpha dystroglycan, antibody blocking studies, and glycan blocking studies all suggest that the O-linked glycans on alpha dystroglycan mediate the binding of extracellular matrix proteins in skeletal muscle. Structural data on laminin G domains and agrin-binding studies also suggest this is the case. Dystroglycan, however, is able to bind proteins via mechanisms that do not involve O-linked glycans. Moreover, laminin and other matrix proteins can bind cell adhesion molecules via their glycan chains. Thus although complex and sometimes not overly convincing, these data suggest that glycosylation plays an important role in dystroglycan binding and function in skeletal muscle.

Animals↗
PubMed2003

Glycobiology of neuromuscular disorders.

There has been a recent explosion in the identification of neuromuscular diseases caused by mutations in genes that affect carbohydrate metabolism or protein glycosylation. A number of these findings relate to defects in the glycosylation of alpha dystroglycan. Alpha dystroglycan is an essential component of the dystrophin-glycoprotein complex, and aberrant glycosylation of alpha dystroglycan is associated with multiple forms of muscular dystrophy in mice and humans. We review the evidence that defects in dystroglycan glycosylation cause muscular dystrophy. In addition, we review evidence that glycobiology is important in other disorders that affect muscle, including hereditary inclusion body myopathy type II and congenital disorders of glycosylation. Finally, we discuss the long-term potential of glycotherapies for muscle disorders.

Animals↗
PubMed2003

Overexpression of the CT GalNAc transferase inhibits muscular dystrophy in a cleavage-resistant dystroglycan mutant mouse.

Transgenic mice that express dystroglycan containing a serine to alanine point mutation at the normal site of cleavage (DG(S654A)) in their skeletal muscles fail to express endogenously cleaved dystroglycan and have muscular dystrophy [Neuromusc. Disord., in press]. Dystrophic DG(S654A) muscles have reduced binding of antibodies, including VIA4-1, that recognize carbohydrate antigens on alpha dystroglycan, a finding similar to muscles in some forms of congenital muscular dystrophy. Here we describe one DG(S654A) transgenic line where VIA4-1 antibody binding is absent in skeletal muscle. In theory, the absence of this carbohydrate antigen should inhibit later glycosylation events that would occur on the structure or structures this antibody binds to. One such modification is likely to be the CT carbohydrate antigen, which is present on alpha dystroglycan in muscles overexpressing the CT GalNAc transferase [Dev. Biol. 242 (2002) 58]. To test the relationship between the VIA4-1 and CT carbohydrate antigens, we made DG(S654A)/CT GalNAc transferase (DG(S654A)/CT) transgenic mice. Surprisingly, dystroglycan was cleaved, and alpha dystroglycan was glycosylated with the VIA4-1 antigen, in DG(S654A)/CT muscles. In addition, muscles in DG(S654A)/CT transgenic mice had little or no evidence of muscular dystrophy when compared to DG(S654A) littermates. These experiments demonstrate that the CT GalNAc transferase can affect the post-translational processing of dystroglycan and the extent of muscular dystrophy even in muscles where the VIA4-1 antigen is not present.

Animals↗
PubMed2003

Inhibition of dystroglycan cleavage causes muscular dystrophy in transgenic mice.

Dystroglycan (DG) is an essential component of the dystrophin-glycoprotein complex, a molecular scaffold that links the extracellular matrix to the actin cytoskeleton. Dystroglycan protein is post-translationally cleaved into alpha dystroglycan, a highly glycosylated peripheral membrane protein, and beta dystroglycan, a transmembrane protein. Despite clear evidence of the importance of dystroglycan and its associated proteins in muscular dystrophy, the purpose of dystroglycan proteolysis is unclear. By introducing a point mutation at the normal site of proteolysis (serine 654 to alanine, DGS654A), we have created a dystroglycan protein that is severely inhibited in its cleavage. Transgenic expression of DGS654A in mouse skeletal muscles inhibited the expression of endogenously cleaved dystroglycan, while overexpression of wild type dystroglycan by similar amounts did not. DGS654A animals had increased serum creatine kinase activity and most muscles had increased numbers of central nuclei. Overexpression of wild type dystroglycan, by contrast, caused no dystrophy by these measures. Dystrophy in DGS654A muscles correlated with reduced binding of antibodies that recognize glycosylated forms of alpha dystroglycan. Lastly, neuromuscular junctions in DGS654A muscles were aberrant in structure. These data show that aberrant processing of the dystroglycan polypeptide causes muscular dystrophy and suggest that dystroglycan processing is important for the proper glycosylation of alpha dystroglycan.

Animals↗
PubMed2003

Identification of peptides that specifically bind Abeta1-40 amyloid in vitro and amyloid plaques in Alzheimer's disease brain using phage display.

The accumulation of the amyloid-beta (Abeta) peptides in amyloid plaques correlates with pathologic changes that occur in the brains of patients with Alzheimer's disease (AD). The ability to directly target reagents to the amyloid form of the Abeta peptide may allow the delivery of neuroprotective agents to make amyloid plaques less toxic, the delivery of amyloid-destroying molecules to eliminate plaques, or the delivery of reagents to prevent amyloid plaque formation. In addition, such reagents may be useful as diagnostic tools to quantitate the extent of amyloid plaque formation in AD patients. As a step toward these goals, we have used phage peptide display technology to identify peptides that bind specifically to the amyloid form of the Abeta(1-40) peptide. Here we identify two 20-amino acid peptides with similar structural features that bind to the amyloid form of Abeta(1-40) but not to monomeric Abeta(1-40). A recombinant form of one of these peptides was produced in Escherichia coli as a fusion protein with thioredoxin. After purification, this reagent bound Abeta(1-40) amyloid in vitro with a K(d) of 60 nM and specifically labeled amyloid plaques in AD brains. A chemically synthesized version of this peptide also bound Abeta(1-40) amyloid and specifically stained amyloid plaques in AD brain. These peptide sequences represent new potential carrier molecules to deliver medicines to amyloid plaques in AD patients and to image plaques in AD brains.

Alzheimer Disease↗
PubMed2003

Role of transcription factors in skeletal muscle and the potential for pharmacological manipulation.

Our understanding of the role of transcription factors in skeletal muscle vastly exceeds our ability to manipulate this class of proteins for therapeutic benefit. Transcription factors responsible for controlling the fate, growth, migration, proliferation, differentiation and regeneration of muscle cells have been identified, and additional factors involved in these processes continue to be discovered. These factors are often involved in multiple steps in muscle differentiation and can have redundant activities. As such, a detailed understanding of their intermolecular interactions and the gene programs they control is essential to the rational design of therapeutics. Mutations in transcription factors cause a number of muscle disorders. Moreover, the manipulation of transcriptional signals holds the promise of treating muscle diseases by exploiting the ability of muscle cells to regenerate after injury. Finally, several proteins have recently been shown to inhibit muscular dystrophy in mouse models. Because some of these proteins are enriched at the neuromuscular synapse, the manipulation of factors governing synaptic transcription is a promising new approach to the treatment of muscular dystrophy.

Acetyltransferases↗
PubMed2002

Definition of pre- and postsynaptic forms of the CT carbohydrate antigen at the neuromuscular junction: ubiquitous expression of the CT antigens and the CT GalNAc transferase in mouse tissues.

At the rodent neuromuscular junction, the synaptic expression of the CT carbohydrate antigens is defined by the binding of two monoclonal antibodies, CT1 and CT2. CT1 preferentially stains the presynaptic membrane, while CT2 preferentially stains the postsynaptic apparatus. Here we show that the differential subsynaptic distribution of these antigens is due to a preference of CT1 for structures containing N-acetyl neuraminic acid (NeuAc) and a preference of CT2 for structures containing N-glycolyl neuraminic acid (NeuGc). This was found to be the case both in binding to cultured myotubes, where NeuAc/NeuGc levels were manipulated by feeding acetylated N-acetyl mannosamine precursors, and in binding to purified GM2 ganglioside containing either NeuAc or NeuGc. At human neuromuscular junctions, where the enzymatic machinery to make NeuGc is absent [Proc. Natl. Acac. Sci. USA 95 (1998) 11751], CT1 and GM2(NeuAc) antibodies stained, while CT2 did not. Thus, the N-glycolyl modification of sialic acid helps to define the differential distribution of the CT antigens at the rodent neuromuscular junction, and this difference is lost in humans. In addition, sulfatase and 9-O-acetylesterase treatment of cells or tissues increased the amount of CT1 and CT2 antibody binding, with sulfatase differentially unmasking CT antigen expression on particular glycoproteins. Despite its uniquely synaptic localization in skeletal muscle, the CT antigens and the CT GalNAc transferase are ubiquitously expressed in other mouse tissues, including brain, spinal cord, and peripheral nerve. One of the proteins that can be co-purified with a CT-reactive glycoprotein is alpha dystroglycan. These data better define the sub-synaptic structures of the CT carbohydrate antigens at the neuromuscular junction and demonstrate their ubiquitous presence in mouse tissues, including the brain.

Animals↗
PubMed2002

Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice.

Duchenne muscular dystrophy (DMD) is a congenital X-linked myopathy caused by lack of dystrophin protein expression. In DMD, the expression of many dystrophin-associated proteins (DAPs) is reduced along the sarcolemmal membrane, but the same proteins remain concentrated at the neuromuscular junction where utrophin, a dystrophin homologue, is expressed [Matsumura, K., Ervasti, J. M., Ohlendieck, K., Kahl, K. D. & Campbell, K. (1992) Nature (London) 360, 588-591]. This outcome has led to the concept that ectopic expression of a "synaptic scaffold" of DAPs and utrophin along myofibers might compensate for the molecular defects in DMD. Here we show that transgenic overexpression of the synaptic CT GalNAc transferase in the skeletal muscles of mdx animals (mdx/CT) increases the expression of utrophin and many DAPs, including dystroglycans, sarcoglycans, and dystrobrevins, along myofibers. Protein expression of utrophin and DAPs was equal to or above that of wild-type mice. In addition, alpha-dystroglycan was glycosylated with the CT carbohydrate antigen in mdx/CT but not in mdx muscles. mdx/CT mice have little or no evidence of muscular dystrophy by several standard measures; Serum creatine kinase levels, percentage of centrally located myofiber nuclei, and variance in myofiber diameter in mdx/CT muscles were dramatically reduced compared with mdx mice. These data suggest that ectopic expression of the CT GalNAc transferase creates a functional dystrophin-related complex along myofibers in the absence of dystrophin and should be considered as a target for therapeutic intervention in DMD.

Animals↗
PubMed2002

Overexpression of the CT GalNAc transferase in skeletal muscle alters myofiber growth, neuromuscular structure, and laminin expression.

Carbohydrates have been shown to mediate or modulate a number of important events in the development of the nervous system; however, there is little evidence that they participate directly in the development of synapses. One carbohydrate structure that is likely to be important in synaptic development of the neuromuscular junction is the CT carbohydrate antigen [GalNAcbeta1,4[NeuAcalpha2,3]Galbeta1(-3GalNAc or -4GlcNAc)]. The synaptic localization of the CT antigen is due to the presence of the terminal beta1,4 GalNAc linkage, and such linkages are localized to the neuromuscular junction in many species. Here we show that an enzyme that can create the synaptic CT structure, the CT GalNAc transferase, is also confined to the neuromuscular junction in mice. Using transgenic mice, we show that overexpression of the CT GalNAc transferase in extrasynaptic regions in skeletal myofibers caused as much as a 60% reduction in the diameter of adult myofibers and an order of magnitude increase in satellite cells. Neuromuscular junctions of transgenic mice had severely reduced numbers of secondary folds, Schwann cell processes were present in the synaptic cleft, and secondary folds were often misaligned with active zones. In addition, multiple presynaptic specializations occurred on individual myofibers. In addition, some normally synaptic proteins, including laminin alpha4, laminin alpha5, utrophin, and NCAM, were expressed along extrasynaptic regions of myofibers. One of the muscle proteins that displayed increased glycosylation with the CT antigen in the transgenic mice was alpha-dystroglycan. These experiments provide the first in vivo evidence that a synaptic carbohydrate antigen has important roles in the development of the neuromuscular synapse and suggest that the CT antigen is involved in controlling the expression of synaptic molecules.

Amino Acid Sequence↗
PubMed2002

Modulation of agrin binding and activity by the CT and related carbohydrate antigens.

Agrin is a nerve-derived signal that is essential for the proper organization of postsynaptic acetylcholine receptors (AChRs) at the vertebrate neuromuscular junction. It is likely that carbohydrates play a significant role in regulating agrin activity, as agrin binds multiple glycan structures and is itself a highly glycosylated protein. Here we provide support for this contention by showing that agrin can be modified with the CT antigen, a carbohydrate structure expressed at the neuromuscular junction, and by describing the resulting changes in agrin binding to neoglycoconjugates and cultured myotubes, as well as changes in agrin-dependent AChR clustering. Glycosylation of agrin with the CT antigen required the mucin domain and the dystroglycan/heparin-binding domain. The presence of the mucin domain lowered agrin binding to several N-acetyllactosaminyl-containing saccharides and C2 myotubes and lowered agrin activity in AChR clustering. Glycosylation of agrin with the CT antigen, by contrast, increased agrin binding to myotubes and potentiated its AChR clustering activity at subsaturating concentrations. Last, sialylated and nonsialylated variants of N-acetyllactosamine differentially modulated AChR clustering and agrin activity, and these changes correlated with the ability of MuSK, an agrin-stimulated kinase, to bind to these structures. These experiments demonstrate that the glycosylation state of agrin affects its activity and suggest a role for the CT antigen in modulating agrin function.

Agrin↗
PubMed2002

Glycobiology of the synapse.

Synapses are the fundamental units of connectivity that link together the nervous system. Lectin studies from 30 years ago suggested that specific glycans are concentrated at neuromuscular synapses in the peripheral nervous system and at excitatory synapses in the brain. Subsequent studies have confirmed that particular glycan structures are localized at these synapses, including polysialic acid, high mannose, the cytotoxic T cell antigen, and forms of heparan sulfate. Though the role of these molecules in synapse formation and function is still poorly understood, there is increasing evidence that the function of agrin, a synaptogenic factor in neuromuscular formation, is modulated by several glycans. In addition, the recent generation of ST8SiaIV null mice strongly suggests a role for polysialic acid in synaptic plasticity in the some regions of the central nervous system.

Animals↗
PubMedDate not supplied

Glycobiology of the neuromuscular junction.

Most molecules that are present at synapses are glycosylated with carbohydrates, and some carbohydrate structures are themselves uniquely synaptic in their localization. Thus, proteins or lipids at the synapse may bear distinct carbohydrates that alter their localization or function. Here, I will review the evidence that there are unique synaptic carbohydrates at the neuromuscular junction. Then, I will review the evidence that such carbohydrates can affect the function of synaptic proteins, with particular attention to agrin, dystroglycan, and the neural cell adhesion molecule (NCAM). Finally, I will review recent data that demonstrates a role for one carbohydrate structure, the cytotoxic T cell (CT) antigen, in neuromuscular development. These studies suggest that glycosylation is an important modification to consider in studies of synapse formation and function.

Animals↗