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)

1. AMP, ADP, ATP, IMP, GDP, GTP and adenylosuccinate have been measured by high pressure liquid chromatography in three types of animal muscular dystrophy and in a human patient with Duchenne muscular dystrophy. 2. Abnormalities in nucleotide content varied from one dystrophy to another. 3. In each case, however, the ratio [total adenine nucleotide + IMP]/[total guanine nucleotides] was lower in dystrophic muscle, even when severely exercised or ischaemic muscles were used. 4. The practical advantages of this assay for diagnosis of muscular dystrophy are discussed.
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PMID:The purine nucleotide profile in mouse, chicken and human dystrophic muscle: an abnormal ratio of inosine plus adenine nucleotides to guanine nucleotides. 705 28

Myofibrillar protein degradation was measured in 4-week-old normal (line 412) and genetically muscular-dystrophic (line 413) New Hampshire chickens by monitoring the rates of 3-methylhistidine excretion in vivo and in vitro. A method of perfusing breast and wing muscles was developed and the rate of 3-methylhistidine release in vitro was measured between 30 and 90min of perfusion. During this perfusion period, 3-methylhistidine release from the muscle preparation was linear, indicating that changes in 3-methylhistidine concentration of the perfusate were the result of myofibrillar protein degradation. Furthermore, the viability of the perfused muscle was maintained during this interval. After 60min of perfusion, ATP, ADP and creatine phosphate concentrations in pectoral muscle were similar to muscle freeze-clamped in vivo. Rates of glucose uptake and lactate production were constant during the perfusion. In dystrophic-muscle preparations, the rate of 3-methylhistidine release in vitro (nmol/h per g of dried muscle) was elevated 2-fold when compared with that in normal muscle. From these data the fractional degradation rates of myofibrillar protein in normal and dystrophic pectoral muscle were calculated to be 12 and 24% respectively. Daily 3-methylhistidine excretion (nmol/day per g body wt.) in vivo was elevated 1.35-fold in dystrophic chickens. Additional studies revealed that the anti-dystrophic drugs diphenylhydantoin and methylsergide, which improve righting ability of dystrophic chickens, did not alter 3-methylhistidine release in vitro. This result implies that changes in myofibrillar protein turnover are not the primary lesion in avian muscular dystrophy. From tissue amino acid analysis, the myofibrillar 3-methylhistidine content per g dry weight of muscle was similar in normal and dystrophic pectoral muscle. More than 96% of the 3-methylhistidine present in pectoral muscle was associated with the myofibrillar fraction. Dystrophic myofibrillar protein contained significantly less 3-methylhistidine (nmol/g of myofibrillar protein) than protein from normal muscle. This observation supports the hypothesis that there may be a block in the biochemical maturation and development of dystrophic muscle after hatching. Free 3-methylhistidine (nmol/g wet wt.) was elevated in dystrophic muscle, whereas blood 3-methylhistidine concentrations were similar in both lines. In summary, the increased myofibrillar protein catabolism demonstrated in dystrophic pectoral muscle correlates with the increased lysosomal cathepsin activity in this tissue as reported by others.
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PMID:Myofibrillar protein degradation in the chicken. 3-Methylhistidine release in vivo and in vitro in normal and genetically muscular-dystrophic chickens. 731 97

Myotonic muscular dystrophy (MyD) is a systemic genetic disorder that is thought to result from a generalized cellular membrane defect although the exact nature of this defect is unknown. This study examines two calcium-dependent membrane processes that have been observed in erythrocytes from healthy individuals: calcium-stimulated phosphatidic acid accumulation and calcium-induced potassium leak. We find that erythrocytes from MyD patients, in contrast to controls, have markedly impaired phosphatidic acid accumulations while maintaining normal potassium leaks. The calcium uptakes and ATP contents of MyD erythrocytes are not different from controls. We conclude that phospholipid metabolism is altered in MyD erythrocytes. The specificity of this abnormality and its relationship to altered muscular function are not known.
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PMID:Myotonic muscular dystrophy: defective phospholipid metabolism in the erythrocyte plasma membrane. 741 May 51

We studied the effect of mitochondrial extracts of skeletal muscle obtained from patients with Duchenne's muscular dystrophy (DMD) on calmitine of the mitochondrial matrix isolated from skeletal muscle of control mice. Our results in vitro clearly show that calmitine of the mitochondrial matrix of control muscle was degraded in the presence of mitochondrial extracts of muscle from DMD patients. The diseased muscle apparently contains an abnormal calmitine-specific proteolytic factor responsible for the calmitine deficiency previously observed in this tissue. As calmitine binds calcium and probably plays a role in regulating the balance of bound and free calcium within mitochondria, a calmitine deficiency could result in an overload of mitochondrial free calcium. Certain enzymes involved in ATP synthesis would be inhibited, resulting in the muscular degeneration characteristic of this myopathy. Our results suggest the cause of mitochondrial calcium overload and the events leading to muscular degeneration in this disease model. Abnormal protease activity could be the factor triggering all of these processes in the DMD patient. These findings suggest that it may now feasible to search for an efficient pharmacologic treatment for DMD.
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PMID:Skeletal muscle of patients with Duchenne's muscular dystrophy: evidence of a mitochondrial proteolytic factor responsible for calmitine deficiency. 866 Mar 74

In muscular dystrophy (MD) the imbalance between muscle protein synthesis and degradation may be an important factor leading to muscle wasting. The three major pathways of muscle proteolysis identified in skeletal muscle are: the lysosomal cathepsin pathway, the calcium-dependent calpain pathway, and the ATP-dependent ubiquitin pathway. Insulin-like growth factor I (IGF-I) and a high-protein diet (HPD) have been shown to reduce proteolysis in skeletal muscle. We examined the effect of 6 weeks of recombinant human IGF-I (rhIGF-I) alone or in combination with HPD treatment on the proteolytic pathways in skeletal muscle of 129 ReJ dystrophic (dy) mice. (A group of normal (Norm) nondystrophic (129 J) mice were included as controls). Untreated dy mice exhibited increased net proteolysis (P < 0.05), elevated net calpain activity (P < 0.01), and increased ubiquitin levels when compared to control mice (P < 0.05). Our evidence suggests that HPD and rhIGF-I decrease proteolysis in the 129 ReJ dy mouse. This effect appears attributable, at least in part, to reduced calpain-mediated myofibrillar breakdown (P < 0.05) due to decreased calpain autolysis or increased calpastatin levels. In contrast to calpain, cathepsin B activity was increased in HPD and rhIGF-I + HPD-treated dy muscle (P < 0.05) and unaltered in the rhIGF-I treated animals. Levels of free and protein-conjugated ubiquitin were also increased in rhIGF-I, and rhIGF-I + HPD treated dyanimals (P < 0.05). The amelioration of muscle wasting in the 129 ReJ dy model by HPD and/or rhIGF-I may have potential implications in the treatment of human MD.
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PMID:Insulin-like growth factor-I and high protein diet decrease calpain-mediated proteolysis in murine muscular dystrophy. 964 44

In a previous report we suggested that muscle fibers in distal myopathy with rimmed vacuoles (DMRV) were degraded by both lysosomal proteolysis (cathepsins) and Ca2+-dependent, nonlysosomal proteolysis (calpain). Given recent evidence of abnormal ubiquitin accumulation in rimmed vacuoles, we examined the role of the ATP-ubiquitin-dependent proteolytic pathway (proteasomes) in myofiber degradation in this myopathy. Immunohistochemically, proteasomes (26S) were located in the cytoplasm in normal human muscle, but the staining intensity was weak. Quantitative analysis showed more reactivity for proteasomes in DMRV muscles and, to a lesser extent, in muscles from muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis patients. In DMRV, proteasomes often were located within or on the rim of rimmed vacuoles, and in the cytoplasm of atrophic fibers. Ubiquitin accumulation was marked within rimmed vacuoles and was seen less extensively in the cytoplasm of atrophic fibers. The latter proteins colocalized well. In other diseased muscles, proteasomes and ubiquitin showed a positive reaction in the atrophic or necrotic fibers. The results indicate increased proteasome and ubiquitin in these muscle fibers as well as in other diseased muscle fibers. We suggest that the ATP-ubiquitin-proteasome proteolytic pathway as well as the nonlysosomal calpain and the lysosomal proteolytic pathway may participate in the muscle fiber degradation in DMRV.
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PMID:Proteasomes in distal myopathy with rimmed vacuoles. 980 76

Mitochondria, the main source of energy for eukaryotic cells through oxidative phosphorylation, also play a key role in the pathways to cell death. The mode of cell death may be influenced by the availability of ATP, and its very occurrence may critically depend on release of mitochondrial proteins like cytochrome c, apoptosis-inducing factor and possibly caspases 3 and 9. Ca2+-dependent onset of the permeability transition, caused by opening of a cyclosporin A-sensitive pore modulated by cyclophilin D, may play a major role in cell death through ATP depletion, disruption of Ca2+ homeostasis, and release of specific mitochondrial proteins. Dysregulation of Ca2+ homeostasis, proteolysis and a decreased ability to cope with oxidative stress are involved in the pathogenesis of Duchenne's muscular dystrophy downstream of the genetic lesion, and mitochondria appear as likely targets that may amplify the initial insult resulting in the irreversible events leading to cell demise. My colleagues and I are studying the permeability transition in skeletal muscle mitochondria, and we are validating bupivacaine in a short-term model of muscle cell toxicity involving mitochondrial depolarization and pore opening as early events. Specific goals for the future are to further define the role of mitochondria in muscle cell death, with particular emphasis on the role of the permeability transition pore and cyclophilin D, and to develop and test drugs able to affect its course in model systems in vitro and in the mdx mouse, an animal model of Duchenne's muscular dystrophy.
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PMID:Mitochondria in muscle cell death. 1093 59

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

Alpha-Sarcoglycan is a glycoprotein associated with the dystrophin complex at sarcolemma of skeletal and cardiac muscles. Gene defects in alpha-sarcoglycan lead to a severe muscular dystrophy whose molecular mechanisms are not yet clear. A first insight into the function of alpha-sarcoglycan was obtained by finding that it is an ATP-binding protein and that it probably confers ability to hydrolyse ATP to the purified dystrophin complex [Betto, Senter, Ceoldo, Tarricone, Biral and Salviati (1999) J. Biol. Chem. 274, 7907-7912]. In the present study, we present definitive evidence showing that alpha-sarcoglycan is an ATP-hydrolysing enzyme. The appearance of alpha-sarcoglycan protein expression was correlated with the increase in ecto-nucleotidase activity during differentiation of C2C12 cells. Approx. 25% of ecto-nucleotidase activity displayed by the C2C12 myotubes was inhibited by preincubating cells with an antibody specific for the ATP-binding motif of alpha-sarcoglycan. This demonstrates that alpha-sarcoglycan substantially contributes to total ecto-nucleotidase activity of C2C12 myotubes. To characterize further this activity, human embryonic kidney 293 cells were transfected with expression plasmids containing alpha-sarcoglycan cDNA. Transfected cells exhibited a significant increase in the ATP-hydrolysing activity that was abolished by the anti-alpha-sarcoglycan antibody. The enzyme had a substrate specificity for ATP and ADP, did not hydrolyse other triphosphonucleosides, and the affinity for ATP was in the low mM range. The ATPase activity strictly required the presence of both Mg2+ and Ca2+ and was completely inhibited by suramin and reactive blue-2. These results show that alpha-sarcoglycan is a Ca2+, Mg2+-ecto-ATPDase. The possible consequences of the absence of alpha-sarcoglycan activity in the pathogenesis of muscular dystrophy are discussed.
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PMID:Characterization of the ATP-hydrolysing activity of alpha-sarcoglycan. 1503 52

ATP is an important extracellular signaling molecule mediating its effects by activation of P2X and P2Y receptors. P2 receptors are expressed during muscle development, and recent findings demonstrate that ATP can regulate myoblast proliferation and differentiation in vitro. However, the role of purinergic signaling during regeneration of injured skeletal muscle has not been investigated. To examine this process in a clinically relevant system, we used the mouse model of muscular dystrophy (mdx), in which muscle degeneration is rapidly followed by regeneration. The latter process, in vivo muscle regeneration, was the focus of this study, and to study the cellular mechanisms involved in it, a parallel study on normal rat skeletal myoblast cultures was conducted. Using immunohistochemistry, RT-PCR, and electrophysiology, we investigated the expression of the P2X1-7 receptor subtypes and the P2Y1,2,4,6 receptors. Experiments in vitro and in vivo demonstrated the sequential expression of the P2X5, P2Y1, and P2X2 receptors during the process of muscle regeneration. The P2X5 and P2Y1 receptors were expressed first on activated satellite cells, and the P2Y1 receptor was also expressed on infiltrating immune cells. Subsequent P2X2 receptor expression on newly formed myotubes showed significant colocalization with AChRs, suggesting a role in regulation of muscle innervation. Thus, this study provides the first evidence for a role for purinergic signaling in muscle regeneration and raises the possibility of new therapeutic strategies in the treatment of muscle disease.
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PMID:Purinoceptor expression in regenerating skeletal muscle in the mdx mouse model of muscular dystrophy and in satellite cell cultures. 1523 20


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