Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Female Wistar rats were treated orally for 5 days with 80 mg/kg body weight of 2,5-di(tert-butyl)-1,4-hydroquinone (DTBHQ), a microsomal Ca2+ ATPase inhibitor. Motor endplates of the lumbrical muscles were examined by light and electron microscopy. There was a decrease in body weight in the treated rats from the first day after administration, and toxic signs appeared after the third day, such as adoption of a prone position, salivation, lacrymation, and an abnormal gait and/or muscle weakness. No remarkable macroscopic or light microscopic changes were noted in the lumbrical muscles as well as other peripheral nerves of hind legs of the treated rats killed 1 day after the last DTBHQ treatment. Ultrastructurally, neurotoxicity characterized by loss of synaptic vesicles and mitochondria in the motor endplates, and by destruction of the motor terminals was detected in the lumbrical muscles of the treated rats. These results strongly indicate that DTBHQ targets the motor endplates in the rat lumbrical muscles and suggest that the resultant damage is responsible for the appearance of neurological signs, such as an abnormal gait and loss of muscle control.
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PMID:Ultrastructural changes in motor endplates of the lumbrical muscles of rats induced by a microsomal Ca2+ ATPase inhibitor, 2,5-di(tert-butyl)-1,4-hydroquinone. 945 84

Muscle biopsies for histochemical and ultrastructural analysis were obtained from seven critically ill patients admitted to the Intensive Care Unit of the "Domingo Luciani" Hospital, Caracas, Venezuela. The sample included two patients with sepsis of abdominal origin, and five that presented sepsis/MOFS, with renal, hepatic, and respiratory disturbances and muscular weakness. Sections were examined for myosin adenosine triphosphatase (ATPase) after pre-incubation with both acid buffer (pH 4.37 and 4.6) and alkaline buffer (pH 10.3), for reduced nicotinamide dinucleotide diaphorase (NADHd), and for alpha-glycerophosphate dehydrogenase (alpha-GPDH). Sections were stained with hematoxilin and eosin to look for pathological changes and examined with a transmission electron microscope. Skeletal muscle of patients in early stage of sepsis showed a normal aspect with light microscopy, but at the ultrastructural level some of the fibres showed atrophy and some capillaries looked altered. Patients with sepsis/MOFS exhibited an evident muscle disorder with oedema, infiltrate, atrophy and segmental necrosis. All fibre types showed decrease in diameter; specially fibre types IIA and IIB. Intramuscular capillaries were thickened and occluded, indexes of capillarity were slightly reduced, and fibre oxidative activity was decreased. At ultrastructural level fibres showed severe atrophy, contractile system disorganization and segmental necrosis. Capillaries were also altered and the mononuclear cell infiltrate was abundant and represented by macrophages, lymphocytes and mastocytes.
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PMID:Histochemical and ultrastructural study of skeletal muscle in patients with sepsis and multiple organ failure syndrome (MOFS). 947 42

Case 1: A 27-year-old man had a fever of 38 degrees C, followed by acute onset of bilateral upper arm pain. Two days later severe muscle weakness in bilateral upper arms appeared and he was admitted to our hospital. On admission, severe atrophy of the left deltoid and mild atrophy of the right deltoid were observed, with severe muscle weakness in bilateral deltoid and mild weakness in other parts of upper extremities. Tendon reflexes were decreased in the upper extremities. Sensation was intact. CSF showed mild pleocytosis. Nerve conduction velocity was normal and electromyography showed mild NMU decrease in upper extremities. Muscle biopsy of the right deltoid one month after the onset was normal. Muscle weakness began to improve 3 months after the onset, with only mild weakness at 10 months. Case 2: A 60-year-old man had acute onset of left shoulder and upper arm pain, followed by muscle atrophy and weakness of the left upper arm. He showed marked atrophy of the left deltoid, moderate atrophy of the left biceps and left scapular region, and severe muscle weakness in the left upper arm. Deep tendon reflexes were absent in the left upper extremity. Sensation was intact. Nerve conduction velocity was normal and electromyography showed marked NMU decrease in the left upper arm. Muscle biopsy of the left biceps 4 months after the onset showed grouped atrophies on HE staining, type 2 fiber atrophies on routine ATPase staining, and many targetoid atrophic fibers on NADH-TR staining. Muscle weakness began to improve slowly 6 months after the onset, but considerable weakness persisted at 10 months. Detailed muscle biopsy findings in neuralgic amyotrophy have not been documented. Muscle biopsy of Case 2 showed marked neurogenic changes compared to Case 1, which may be associated with the difference in clinical course between the two cases.
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PMID:[Two cases of neuralgic amyotrophy]. 986 14

Muscle wasting and weakness are common features of patients with critical illnesses, and may impair their recovery. This study examines whether cytoskeletal and contractile proteins are damaged, and which proteolytic mechanisms might be involved, in the muscle fibre atrophy or necrosis associated with the acute myopathy of critically ill patients. Ninety-eight muscle biopsies were obtained by the conchotome method from 57 critically ill patients and examined morphometrically and by immunohistochemical labelling. Sequential biopsies showed a mean reduction in fibre cross-sectional areas of 3-4% per day. More intense immunolabelling for desmin was seen in the smaller fibres of 52% of the biopsies, while immunolabelling for dystrophin, actin and myosin heavy chains was maintained. Myosin ATPase activity was weak in the smaller fibres in some biopsies, and electron microscopy showed the loss of myosin filaments in atrophic fibres. These changes suggest that loss of the filamentous structure of myosin, without degradation of the immunolabelled epitopes, leads to the collapse of the intermyofibrillar desmin network. Fibres with abnormal desmin labelling showed increased cathepsin B, lysozyme and ubiquitin immunolabelling. Nine cases showed increased immunolabelling for heat shock protein 72. The changes in desmin immunolabelling were more prevalent in patients with higher APACHE II scores on admission, but were not related to other clinical features. The results indicate that fibre atrophy is associated with myosin filament depolymerization and the presence of several proteolytic enzymes. In our study, these changes occurred in patients who were critically ill but who did not receive large doses of steroids or neuromuscular blocking agents.
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PMID:Muscle fibre atrophy in critically ill patients is associated with the loss of myosin filaments and the presence of lysosomal enzymes and ubiquitin. 988 61

In recent years, genetic defects of the mitochondrial genome (mtDNA) were shown to be associated with a heterogeneous group of disorders, known as mitochondrial diseases, but the cellular events deriving from the molecular lesions and the mechanistic basis of the specificity of the syndromes are still incompletely understood. Mitochondrial calcium (Ca2+) homeostasis depends on close contacts with the endoplasmic reticulum and is essential in modulating organelle function. Given the strong dependence of mitochondrial Ca2+ uptake on the membrane potential and the intracellular distribution of the organelle, both of which may be altered in mitochondrial diseases, we investigated the occurrence of defects in mitochondrial Ca2+ handling in living cells with either the tRNALys mutation of MERRF (myoclonic epilepsy with ragged-red fibers) or the ATPase mutation of NARP (neurogenic muscle weakness, ataxia and retinitis pigmentosa). There was a derangement of mitochondrial Ca2+ homeostasis in MERRF, but not in NARP cells, whereas cytosolic Ca2+ responses were normal in both cell types. Treatment of MERRF cells with drugs affecting organellar Ca2+ transport mostly restored both the agonist-dependent mitochondrial Ca2+ uptake and the ensuing stimulation of ATP production. These results emphasize the differences in the cellular pathogenesis of the various mtDNA defects and indicate specific pharmacological approaches to the treatment of some mitochondrial diseases.
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PMID:A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. 1042 22

We investigated the biochemical phenotype of the mtDNA T8993G point mutation in the ATPase 6 gene, associated with neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP), in three patients from two unrelated families. All three carried >80% mutant genome in platelets and were manifesting clinically various degrees of the NARP phenotype. Coupled submitochondrial particles prepared from platelets capable of succinate-sustained ATP synthesis were studied using very sensitive and rapid luminometric and fluorescence methods. A sharp decrease (>95%) in the succinate-sustained ATP synthesis rate of the particles was found, but both the ATP hydrolysis rate and ATP-driven proton translocation (when the protons flow from the matrix to the cytosol) were minimally affected. The T8993G mutation changes the highly conserved residue Leu(156) to Arg in the ATPase 6 subunit (subunit a). This subunit, together with subunit c, is thought to cooperatively catalyze proton translocation and rotate, one with respect to the other, during the catalytic cycle of the F(1)F(0) complex. Our results suggest that the T8993G mutation induces a structural defect in human F(1)F(0)-ATPase that causes a severe impairment of ATP synthesis. This is possibly due to a defect in either the vectorial proton transport from the cytosol to the mitochondrial matrix or the coupling of proton flow through F(0) to ATP synthesis in F(1). Whatever mechanism is involved, this leads to impaired ATP synthesis. On the other hand, ATP hydrolysis that involves proton flow from the matrix to the cytosol is essentially unaffected.
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PMID:Catalytic activities of mitochondrial ATP synthase in patients with mitochondrial DNA T8993G mutation in the ATPase 6 gene encoding subunit a. 1066 May 80

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.
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PMID:[A case of acute quadriplegic myopathy]. 1108 98

Mutations in the human TPM3 gene encoding gamma-tropomyosin (alpha-tropomyosin-slow) expressed in slow skeletal muscle fibers cause nemaline myopathy. Nemaline myopathy is a rare, clinically heterogeneous congenital skeletal muscle disease with associated muscle weakness, characterized by the presence of nemaline rods in muscle fibers. In one missense mutation the codon corresponding to Met-8, a highly conserved residue, is changed to Arg. Here, a rat fast alpha-tropomyosin cDNA with the Met8Arg mutation was expressed in Escherichia coli to investigate the effect of the mutation on in vitro function. The Met8Arg mutation reduces tropomyosin affinity for regulated actin 30- to 100-fold. Ca(2+)-sensitive regulatory function is retained, although activation of the actomyosin S1 ATPase in the presence of Ca(2+) is reduced. The poor activation may reflect weakened actin affinity or reduced effectiveness in switching the thin filament to the open, force-producing state. The presence of the Met8Arg mutation severely, but locally, destabilizes the tropomyosin coiled coil in a model peptide, and would be expected to impair end-to-end association between TMs on the thin filament. In muscle, the mutation may alter thin filament assembly consequent to lower actin affinity and altered binding of the N-terminus to tropomodulin at the pointed end of the filament. The mutation may also reduce force generation during activation.
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PMID:Alteration of tropomyosin function and folding by a nemaline myopathy-causing mutation. 1110 25

Neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome and maternally inherited Leigh's syndrome have been associated with T8993G point mutations in the mitochondrial adenosine triphosphatase 6 gene. Typically, NARP syndrome is characterized by developmental delay, seizures, dementia, retinitis pigmentosa, ataxia, sensory neuropathy, and proximal weakness. Usually, there is a correlation between the percentage of mutated mitochondrial DNA and clinical severity, and when mutated mitochondrial DNA is > 90%, it is often seen with Leigh's syndrome. We now report a family with mitochondrial DNA T8993G mutation in eight living members, five with mutant mitochondrial DNA >90% and one with 20% mutant mitochondrial DNA. However, their clinical features include variable combinations of seizures, behavior problems, learning disability, mental retardation, sensorineural deafness, cerebellar ataxia, and proximal muscle weakness. No retinitis pigmentosa was found in all eight living members, including a 56-year-old grandmother. Only one dead female relative was diagnosed with Leigh's syndrome on the neuropathologic examination at age 22 years, when she died of an accident. High mitochondrial DNA T8993G mutation is not always associated with typical features of Leigh's and NARP syndromes.
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PMID:High mitochondrial DNA T8993G mutation (<90%) without typical features of Leigh's and NARP syndromes. 1145 54

Metabolic myopathies are due to deficiencies of energy production involving glycogen, lipid, or mitochondrial metabolism. Deficiency of sarcoplasmic calcium-ATPase is at the origin of Brody's syndrome. Patients may present with exercise intolerance, myoglobinuria or progressive muscle weakness. The first step of diagnosis relies on the performance of in vivo metabolism investigations: forearm or bicycle ergometer exercise tests, phosphorus nuclear magnetic resonance spectroscopy. A few enzymatic defects may be directly measured on blood sampling, but muscle biopsy is necessary in most cases in order to precise the etiology of the metabolic defect through enzymatic assays. We present a description of the main metabolic myopathies with an overview of clinical and laboratory evaluation leading to diagnosis.
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PMID:[Metabolic myopathies in adulthood. Features and clues for diagnosis]. 1179 77


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