Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous investigators have suggested that proteolysis by calpain, a Ca2+-dependent protease, causes muscle fiber degradation in Duchenne and Becker muscular dystrophies (DMD/BMD). Recent evidence indicates that the nonlysosomal ATP-ubiquitin-dependent proteolytic complex (proteasomes) participates in muscle wasting during various catabolic states and in muscle fiber degradation in physiological or pathological conditions. To elucidate the possible role of proteasomes in dystrophic muscles, routine histochemistry and immunohistochemistry of 26S proteasomes were performed on muscle biopsy specimens obtained from patients with various neuromuscular disorders including DMD/BMD, polymyositis (PM), amyotrophic lateral sclerosis, and peripheral neuropathies, and on normal human muscle specimens. Immunohistochemically, proteasomes were located in the cytoplasm in normal human muscle, but their staining intensity was faint. Compared to control muscles, abnormal increases in both proteasomes and ubiquitin were demonstrated mainly in the cytoplasm of necrotic fibers and to a lesser extent in regenerative fibers in DMD/BMD and PM. Non-necrotic, atrophic fibers in all diseased muscles showed moderate or weak immunoreactions for the proteins; their staining intensities were stronger than those of control muscle fibers. Both proteins often colocalized well. Not all dystrophin-deficient muscle fibers showed a strong reaction for proteasomes. Our results showed increased proteasomes in necrotic and regenerative muscle fibers in DMD/ PMD, although this may not be disease-specific up-regulation. We suggest that the ATP-ubiquitin-dependent proteolytic pathway as well as the nonlysosomal calpain pathway may participate in muscle fiber degradation in muscular dystrophy.
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PMID:Proteasome expression in the skeletal muscles of patients with muscular dystrophy. 1107 10

The calpains form a growing family of structurally related intracellular multidomainal cysteine proteinases, which exhibit a catalytic domain distantly related to papain. In contrast to papain, however, their activity in most cases depends on calcium. The calpains are believed to play important roles in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction, but have also been implicated in muscular dystrophy, ischemia, traumatic brain injury, neurodegenerative diseases, rheumatoid arthritis and cataract formation. The best characterized calpains are the ubiquitously expressed mu- and m-calpains, consisting of a common 30 kDa small S-subunit (domains V and VI) and slightly differing 80 kDa large L-subunits (domains I to IV). We have recently determined the 2.3 A structure of recombinant full-length human m-calpain in the absence of calcium, which reveals that the catalytic domain and the two calmodulin-like domains, previously believed to represent the unique calcium switch, are not positioned adjacent to each other, but are separated by the beta-sandwich domain III, which distantly resembles C2 domains. Although the catalytic domain of apocalpain is strongly disrupted compared to papain (which explains its inactivity in the absence of calcium), the crystal structure reveals several sites where calcium could bind, thereby causing a subdomain fusion to form a papain-like catalytic center. All current evidence points to the cooperative interaction of several calcium binding sites. Sites identified include the three EF-hand binding sites in each calmodulin-like domain, the negatively charged segments arranged around the active-site cleft (provided by both catalytic subdomains), as well as an exposed acidic loop of domain III, whose charge compensation could allow the adjacent barrel-like subdomain IIb to move toward the helical subdomain IIa. The Gly-rich S-chain N-terminus and the calcium-loaded acidic loop could target the conventional calpains to cellular/nuclear membranes, thereby explaining their strongly reduced calcium requirement in vivo and in vitro in the presence of acidic phospholipids.
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PMID:Structural basis for possible calcium-induced activation mechanisms of calpains. 1151 28

The calpains form a growing family of structurally related intracellular multidomain cysteine proteinases containing a papain-related catalytic domain, whose activity depends on calcium. The calpains are believed to play important roles in cytoskeletal remodeling processes, cell differentiation, apoptosis and signal transduction, but are also implicated in muscular dystrophy, cardiac and cerebral ischemia, platelet aggregation, restenosis, neurodegenerative diseases, rheumatoid arthritis and cataract formation. The best characterized calpains, the ubiquitously expressed mu- and m-calpains, are heterodimers consisting of a common 30-kDa small and a variable 80-kDa subunit. The recently determined crystal structures of human and rat m-calpain crystallized in the absence of calcium essentially explain the inactivity of the apoform by catalytic domain disruption, indicate several sites where calcium could bind causing reformation of a papain-like catalytic domain, and additionally reveal modes by which phospholipid membranes could reduce the calcium requirement. Current evidence points to a cooperative interaction of several sites, which, upon calcium binding, trigger the reformation of a papain-similar catalytic domain.
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PMID:The structure of calcium-free human m-calpain: implications for calcium activation and function. 1167 52

The X-linked muscle-wasting disease Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin. There is currently no effective treatment for the disease; however, the complex molecular pathology of this disorder is now being unravelled. Dystrophin is located at the muscle sarcolemma in a membrane-spanning protein complex that connects the cytoskeleton to the basal lamina. Mutations in many components of the dystrophin protein complex cause other forms of autosomally inherited muscular dystrophy, indicating the importance of this complex in normal muscle function. Although the precise function of dystrophin is unknown, the lack of protein causes membrane destabilization and the activation of multiple pathophysiological processes, many of which converge on alterations in intracellular calcium handling. Dystrophin is also the prototype of a family of dystrophin-related proteins, many of which are found in muscle. This family includes utrophin and alpha-dystrobrevin, which are involved in the maintenance of the neuromuscular junction architecture and in muscle homeostasis. New insights into the pathophysiology of dystrophic muscle, the identification of compensating proteins, and the discovery of new binding partners are paving the way for novel therapeutic strategies to treat this fatal muscle disease. This review discusses the role of the dystrophin complex and protein family in muscle and describes the physiological processes that are affected in Duchenne muscular dystrophy.
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PMID:Function and genetics of dystrophin and dystrophin-related proteins in muscle. 1191 91

Dystrophin, a product of a gene located at the chromosome Xp21 locus, is a cytoskeletal protein expressed in skeletal, cardiac and smooth muscles, and in the brain, and is located on the inner site of the plasma membrane. Dystrophin in the skeletal muscles is absent or appears only in traces in Duchenne dystrophy, it is reduced with normal/changed molecular weight in Becker dystrophy and it is absent/reduced in mdx mice. It is supposed that dystrophin acts either as a structural scaffold that supports mechanical stress in sarcolemma, or participates in regulating intracellular Ca2+ level. There are also data indicating that dystrophin takes part in force and signal transduction processes, in the aggregation of neurotransmitter receptors, and prevents an excessive generation of reactive oxygen free radical species. The main hypotheses indicate that lack of structural support, an excessive influx of Ca2+ ions into the muscle cell, or a combination of both these mechanisms in dystrophin-deficient muscle fibres, is responsible for muscle pathology in progressive muscular dystrophy. There are arguments supporting these hypotheses. There are, however, also data indicating that the presented arguments are doubtful. Despite recent advances in the knowledge of the pathogenesis of muscular dystrophies and the advent of modern techniques, we are still very far away from understanding what is the real function of dystrophin in muscle.
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PMID:Controversies about the function of dystrophin in muscle. 1192 96

Mutations in dysferlin, a novel membrane protein of unknown function, lead to muscular dystrophy. Myoferlin is highly homologous to dysferlin and like dysferlin is a plasma membrane protein with six C2 domains highly expressed in muscle. C2 domains are found in a variety of membrane-associated proteins where they have been implicated in calcium, phospholipid, and protein-binding. We investigated the pattern of dysferlin and myoferlin expression in a cell culture model of muscle development and found that dysferlin is expressed in mature myotubes. In contrast, myoferlin is highly expressed in elongated "prefusion" myoblasts and is decreased in mature myotubes where dysferlin expression is greatest. We tested ferlin C2 domains for their ability to bind phospholipid in a calcium-sensitive manner. We found that C2A, the first C2 domain of dysferlin and myoferlin, bound 50% phosphatidylserine and that phospholipid binding was regulated by calcium concentration. A dysferlin point mutation responsible for muscular dystrophy was engineered into the dysferlin C2A domain and demonstrated reduced calcium-sensitive phospholipid binding. Based on these data, we propose a mechanism for muscular dystrophy in which calcium-regulated phospholipid binding is abnormal, leading to defective maintenance and repair of muscle membranes.
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PMID:Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. 1195 63

This study aims to investigate the sodium/calcium exchanger expression in human co-cultured skeletal muscle cells and to compare the effects of Na(+)/Ca(2+) exchange activity in normal and dystrophic (Duchenne's muscular dystrophy) human co-cultured myotubes. For this purpose, variations of intracellular calcium concentration ([Ca(2+)](int)) were monitored, as the variations of the fluorescence ratio of indo-1 probe, in response to external sodium depletion. External sodium withdrawal induced [Ca(2+)](int) rises within several seconds in both normal and Duchenne's muscular dystrophy myotubes. These Na(+)-free-induced [Ca(2+)](int) elevations were attributed to the reverse mode of the Na(+)/Ca(2+) exchange mechanism since the phenomenon was dependent on extracellular calcium concentration ([Ca(2+)](ext)), and since it was sensitive to external Ni(2+) ions. Amplitudes of Na(+)-free-induced [Ca(2+)](int) rises were significantly greater in Duchenne's muscular dystrophy cells than in normal ones. Such a difference disappeared when the sarcoplasmic reticulum was pharmacologically blocked, suggesting that the reverse mode of the Na(+)/Ca(2+) exchange mechanism was able to generate enhanced calcium-induced calcium-release in Duchenne's muscular dystrophy myotubes. Immunostaining images of Na(+)/Ca(2+) exchanger (NCX) isoforms, obtained by confocal microscopy, revealed the presence of NCX1 and NCX3 at the sarcolemmal level of both normal and Duchenne's muscular dystrophy myotubes. No differences were observed in the location of NCX isoforms expression between normal and Duchenne's muscular dystrophy co-cultured myotubes.
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PMID:Na(+)/Ca(2+) exchange in human myotubes: intracellular calcium rises in response to external sodium depletion are enhanced in DMD. 1220 36

Duchenne muscular dystrophy is caused by mutations in the gene encoding dystrophin, a 427 kd protein normally found at the cytoplasmic face of the sarcolemma. In normal muscle, dystrophin is associated with a multimolecular glycoprotein complex. Primary mutations in the genes encoding members of this glycoprotein complex are also associated with muscular dystrophy. The dystrophin-glycoprotein complex provides a physical linkage between the internal cytoskeleton of myofibers and the extracellular matrix, but the precise functions of the dystrophin-glycoprotein complex remain uncertain. In this review, five potential pathogenetic mechanisms implicated in the initiation of myofiber injury in dystrophin-glycoprotein complex deficiencies are discussed: (1) mechanical weakening of the sarcolemma, (2) inappropriate calcium influx, (3) aberrant cell signaling, (4) increased oxidative stress, and (5) recurrent muscle ischemia. Particular emphasis is placed on the multifunctional nature of the dystrophin-glycoprotein complex and the fact that the above mechanisms are in no way mutually exclusive and may interact with one another to a significant degree.
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PMID:Molecular pathophysiology of myofiber injury in deficiencies of the dystrophin-glycoprotein complex. 1240 21

Limb girdle muscular dystrophy type 2A is linked to a skeletal muscle-specific calpain isoform known as p94. Isolation of the intact 94-kDa enzyme has been difficult to achieve due to its rapid autolysis, and uncertainty has arisen over its Ca2+-dependence for activity. We have expressed a C-terminally truncated form of the enzyme that comprises the protease core (domains I and II) along with its insertion sequence, IS1, and N-terminal leader sequence, NS. This 47-kDa p94I-II mini-calpain was stable during purification. In the presence of Ca2+, p94I-II cleaved itself within the NS and IS1 sequences. Mapping of the autolysis sites showed that NS and IS1 have the potential to be removed without damage to the protease core. Ca2+-dependent autolysis must be an intramolecular event because the inactive p94I-II C129S mutant was not cleaved by incubation with wild-type p94I-II. In addition, the rate of autolysis of p94I-II was independent of the concentration of the enzyme.
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PMID:The protease core of the muscle-specific calpain, p94, undergoes Ca2+-dependent intramolecular autolysis. 1248

In the muscular dystrophic (mdx) mouse, which is characterized by deficient dystrophin expression and provides a model of Duchenne's muscular dystrophy, we previously demonstrated marked central nervous system alterations and in particular a quantitative reduction of corticospinal and rubrospinal neurons and pathologic changes of these cells. Prompted by these findings and in view of the relations between calcium ions and dystrophin, we analyzed with immunohistochemistry the neurons containing the calcium-binding proteins parvalbumin, calbindin D28k, and calretinin in cortical areas and brainstem nuclei of mdx mice. In the sensorimotor cortex, parvalbumin-positive and calbindin-positive neurons, which represent a subset of cortical interneurons, were significantly more numerous in mdx mice than in wild-type ones. In addition, the laminar distribution of parvalbumin-positive neurons in the motor and somatosensory cortical areas of mdx mice was altered with respect to wild-type animals. No alterations in the number and distribution were found in the parvalbumin- or calbindin-expressing cell populations of the visual and anterior cingulate cortices of mdx mice. The pattern of calretinin immunoreactivity was normal in all investigated cortical areas. The cell populations containing either calcium-binding protein were similar in brainstem nuclei of mdx and wild-type mice. The present findings demonstrated selective changes of subsets of interneurons in the motor and somatosensory cortical areas of mdx mice. Therefore, the data showed that, in the cortices of these mutant animals, the previously demonstrated pathologic changes of corticospinal cell populations are accompanied by marked alterations in the local circuitry.
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PMID:Cortical and brainstem neurons containing calcium-binding proteins in a murine model of Duchenne's muscular dystrophy: selective changes in the sensorimotor cortex. 1250 13


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