Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.3 (diaphorase)
 5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deltoid muscle was removed at motor point biopsy from 10 female relatives of patients with Duchenne muscular dystrophy and from seven others, with no evidence of neuromuscular disease. Transverse cryostat sections of the muscle from each case were stained for reduced diphosphopyridine nucleotide diaphorase and it was found that all contained varying numbers of degenerating type 1 fibres. The percentage of abnormal fibres in the type 1 fibre population was then calculated for each case and it was found that the muscles from the patients with dystrophic relatives contained considerably higher percentages of abnormal fibres, which also showed more severe degeneration, than did the muscles from the normal cases. There was no absolute correlation between serum creatine kinase levels and degree of pathological change, though patients with the most severe changes in their muscles had abnormally high serum creatine kinase levels. It is suggested that histochemical studies could be a useful addition to the present diagnostic tests for the carrier state in Duchenne muscular dystrophy.
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PMID:Histochemically demonstrable fibre abnormalities in normal skeletal muscle and in muscle from carriers of Duchenne muscular dystrophy. 432 68

(1) Biopsies from the gastrocnemius muscle of patients with Duchenne dystrophy were partitioned into a myofibrillar plus nuclear fraction, a mitochondrial fraction and a supernatant fraction. The fractions were assayed for mitochondrial enzymes and protein, in order to obtain information about the integrity of mitochondrial structure and function. Muscles from boys and adults without neuromuscular disease were treated likewise. (2) In adults, muscle possesses a significantly higher specific activity (on protein basis) of monoamine oxidase and rotenone-insenitive NADH-cytochrome c reductase (RINCR) than in boys. In childhood, monoamine oxidase activity increases with age. At the age of 5 yr, the specific activity is 50% of the adult value. RINCR activity is constant in childhood. With adolescence it increases from 20 +/- 2 (SEM) to 35 +/- 6 mumoles cytochrome c reduced per min per g protein, and it remains at this level. Palmitoyl-CoA synthetase activity remains constant with age. (3) In Duchenne dystrophy the extractable protein content from muscle is decreased to 75%. The specific activities of the matrix enzymes propionyl-CoA carboxylase and glutamate dehydrogenase are 1.8 and 2.8 times increased, the inner membrane enzyme cytochrome c oxidase is 2.8 times increased, the inner membrane enzyme cytochrome c oxidase is 2.8 times increased. Of the outer membrane enzymes RINCR is 2.0 times increased, while palmitoyl-CoA synthetase is not changed in acitivity. In Duchenne dystrophy monoamine oxidase activity also increases with age. In part this may be due to mitochondria from adipose tissue and macrophages, which are increasingly present in older patients. The specific activities of enzymes with a predominant cytosolic localisation, creatine kinase and adenylate kinase, are increased by a factor of 1.5 and 1.7. (4) The subcellular distribution of the studied enzymes in human skeletal muscle was found to be similar as in animal studies. In mitochondrial fractions from Duchenne patients the recoveries of the following enzymes are decreased: glutamate dehydrogenase (from 25 to 9%), creatine kinase (1.1-0.66%), adenylate kinase (0.44-0.22%), hexokinase (7.1-2.7%), monoamine oxidase (36-21%), RINCR (30-17%), and palmitoyl-CoA synthetase (40-21%). The recoveries of last 3 mitochondrial outer membrane enzymes in the supernatant fractions are correspondingly increased. These results indicate an increased fragility of the mitochondrial membranes in dystrophic muscles. (5) The reported changes are clearly evident in a one-year-old patient, which indicates that the mitochondria are involved early in the disease process.
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PMID:Early changes of muscle mitochondria in Duchenne dystrophy. Partition and activity of mitochondrial enzymes in fractionated muscle of unaffected boys and adults and patients. 624 85

Intracellular pH, ratios of phosphocreatine (PCr) to ATP and PCr to inorganic phosphate (Pi) as well as isometric tension were measured during 1 Hz sciatic nerve stimulation and during recovery in the calf muscles of mdx (a model of Duchenne muscular dystrophy) and control mice. Tension did not decline significantly in either strain. The ratio of PCr/(PCr + Pi) was significantly reduced in mdx as against control muscle during exercise and recovery, but the ratio of PCr/ATP and the half-time for PCr recovery were similar in both strains. A reduction in the maximal activities of succinate dehydrogenase and succinate-cytochrome c reductase suggests that mitochondrial metabolism may be impaired. The similarity in PCr recovery times suggests that the muscle has adapted, making any impairment of oxidative metabolism negligible in the intact system. The rate of pH recovery is prolonged in mdx muscle and provides strong evidence for a decline in the capacity of dystrophic muscle to extrude proton equivalents. These data are compared with a previous study which used 10 Hz stimulation and also observed a slow pH recovery. The slow pH recovery could be explained by an elevation in intracellular sodium.
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PMID:Exercise metabolism in Duchenne muscular dystrophy: a biochemical and [31P]-nuclear magnetic resonance study of mdx mice. 809 27

Recently, it has been shown that in human striated muscle the signalling enzyme, brain-type nitric oxide synthase I (NOS I), is associated with the sarcolemma and complexes with dystrophin and/or members of the dystrophin complex. In order to find out whether there exists a regular association between NOS I and the complex, muscle biopsies from patients with various muscle disorders were analysed by enzyme histochemistry and immunohistochemistry. In patients suffering from Duchenne muscular dystrophy, and to a lesser extent in those with Becker-type dystrophy, NOS I and dystrophin complex components were absent or drastically reduced in the sarcolemma region. In other dystrophies, as well as in metabolic and inflammatory myopathies, NOS I and dystrophin complex constituents were expressed normally, while in the case of neurogenic diseases leading to denervation atrophy and especially congenital idiopathic clubfoot, the immunohistochemical patterns of the distribution of the dystrophin complex constituents were normal, but NOS I activity and protein were deficient or dramatically diminished. The results can be interpreted as indicating that, in general, NOS I targeting to the sarcolemma is dependent on particular members of the dystrophin complex, such as alpha-1 syntrophin, yet the expression and/or positioning of NOS I may be under the control of further factors, probably of neurogenic origin. NOS I-associated diaphorase may thus be a useful complementary tool in the diagnosis of muscle disorders.
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PMID:Absence of nitric oxide synthase I despite the presence of the dystrophin complex in human striated muscle. 914 66

Recently, it has been shown for mouse skeletal muscle that caveolin-3 is localized in the sarcolemma and cofractionates with the original dystrophin complex (DC). In order to find out whether caveolin-3 is a further component of the recently established and enlarged nitric oxide synthase (NOS) I-DC and whether members of this complex interact with and are potentially regulated by caveolin-3, mammalian and non-mammalian healthy and diseased (dystrophic) skeletal muscles were investigated using caveolin-3, NOS I, DC components and myosin immunohistochemistry as well as NOS I-associated diaphorase histochemistry. In healthy mammalian skeletal muscle, caveolin-3 was colocalized with the DC components in all extra- and intrafusal fibers. By contrast, NOS I was absent in type I extrafusal fibers of certain species. In patients with Duchenne muscular dystrophy and mdx mice the components of the NOS I-DC were not detected in all extra- and intrafusal fiber types, while caveolin-3 was found unchanged. In healthy non-mammalian skeletal muscle, i.e. of birds, reptiles and fishes, caveolin-3 immunoreactivity was lacking in the sarcolemma as was alpha-sarcoglycan; the other NOS I-DC components were either present or absent. In conclusion, although caveolin-3 is localized in the sarcolemma of mammalian myofibers, there are differences in the microarchitecture of the components of the DC complex and of caveolin-3 which does not appear to be linked with the NOS I-DC. Potential regulatory interactions between caveolin-3 and NOS I may nevertheless exist in those fibers where both molecules are colocalized. The absence of caveolin-3 and alpha-sarcoglycan immunoreactivities in non-mammalian myofibers may suggest that the functions of these proteins are subserved by other components of NOS I-DC complex.
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PMID:Caveolin-3 and nitric oxide synthase I in healthy and diseased skeletal muscle. 954 84

Although Duchenne muscular dystrophy is primarily classified as a neuromuscular disease, cardiac complications play an important role in the course of this X-linked inherited disorder. The pathobiochemical steps causing a progressive decline in the dystrophic heart are not well understood. We therefore carried out a fluorescence difference in-gel electrophoretic analysis of 9-month-old dystrophin-deficient versus age-matched normal heart, using the established MDX mouse model of muscular dystrophy-related cardiomyopathy. Out of 2,509 detectable protein spots, 79 2D-spots showed a drastic differential expression pattern, with the concentration of 3 proteins being increased, including nucleoside diphosphate kinase and lamin-A/C, and of 26 protein species being decreased, including ATP synthase, fatty acid binding-protein, isocitrate dehydrogenase, NADH dehydrogenase, porin, peroxiredoxin, adenylate kinase, tropomyosin, actin, and myosin light chains. Hence, the lack of cardiac dystrophin appears to trigger a generally perturbed protein expression pattern in the MDX heart, affecting especially energy metabolism and contractile proteins.
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PMID:Proteomic Profiling of the Dystrophin-Deficient MDX Heart Reveals Drastically Altered Levels of Key Metabolic and Contractile Proteins. 2050 50

High intensity training induces muscle damage in dystrophin-deficient mdx mice, an animal model for Duchenne muscular dystrophy. However, low intensity training (LIT) rescues the mdx phenotype and even reduces the level of protein carbonylation, a marker of oxidative damage. Until now, beneficial effects of LIT were mainly assessed at the physiological level. We investigated the effects of LIT at the molecular level on 8-week-old wild-type and mdx muscle using 2D Western blot and protein-protein interaction analysis. We found that the fast isoforms of troponin T and myosin binding protein C as well as glycogen phosphorylase were overcarbonylated and downregulated in mdx muscle. Some of the mitochondrial enzymes of the citric acid cycle were overcarbonylated, whereas some proteins of the respiratory chain were downregulated. Of functional importance, ATP synthase was only partially assembled, as revealed by Blue Native PAGE analysis. LIT decreased the carbonylation level and increased the expression of fast isoforms of troponin T and of myosin binding protein C, and glycogen phosphorylase. In addition, it increased the expression of aconitate hydratase and NADH dehydrogenase, and fully restored the ATP synthase complex. Our study demonstrates that the benefits of LIT are associated with lowered oxidative damage as revealed by carbonylation and higher expression of proteins involved in energy metabolism and muscle contraction. Potentially, these results will help to design therapies for DMD based on exercise mimicking drugs.
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PMID:Low intensity training of mdx mice reduces carbonylation and increases expression levels of proteins involved in energy metabolism and muscle contraction. 2566 Sep 94