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Biomedical subjects

G Karpati

Publications and source records attributed to G Karpati.

At least 19 recordsLinked to original sources
PubMed1992

Loss and renewal of thick myofilaments in glucocorticoid-treated rat soleus after denervation and reinnervation.

Denervation of rat soleus muscle and simultaneous administration of high doses of corticosteroids for 7 days caused marked muscle fiber atrophy and selective loss of thick myofilaments from many muscle fibers by light and electron microscopy. Myosin heavy chain/actin ratios were greatly reduced on polyacrylamide gel electrophoresis. Nerve crush instead of cut permitted reinnervation after 2 weeks and demonstrated the reversibility of the muscle changes within a week after reinnervation. There was formation of new thick filaments and their reintegration into myofibrils without further breakdown, although large areas of Z-disc streaming appeared. The mechanism of A-band breakdown remains obscure, but it presumably starts with limited proteolysis and continues with disaggregation of myosin molecules. This is consistent with our observation that the muscle fibers retain a relatively good reactivity to antibodies against myosin heavy chain 1 week after denervation and corticosteroid administration. A syndrome recalling these experiments is seen in severely asthmatic patients receiving corticosteroids and pharmacologically paralyzed for mechanical respiration.

Actin Cytoskeleton↗
PubMed1992

Quantitative morphometric study of muscle in inclusion body myositis.

Clinical and electromyographic findings do not clearly distinguish inclusion body myositis (IBM) from chronic polymyositis (PM). The rimmed vacuoles and filamentous nuclear and cytoplasmic inclusions that characterize IBM are often sparse and may be overlooked; conversely, these features may occasionally be seen in other diseases. Preliminary studies suggested that muscle fiber hypertrophy occurred more frequently in IBM than in PM. To investigate whether fiber hypertrophy can be used to improve the ability to separate IBM from PM, we report a morphometric analysis of 28 IBM cases, 22 PM and 22 dermatomyositis (DM) cases. The analysis, using a computer automated system, included proportion of hypertrophied fibers and also fiber type proportions, average fiber diameter, proportion of atrophic and angulated fibers, and the co-dispersion index (CDI). The proportion of hypertrophied fibers was greater in IBM than the other two conditions (IBM (mean +/- SEM) 31.0 +/- 4.7% and 12.2 +/- 2.4% for type 1 and type 2 fibers, respectively, compared to 9.8 +/- 3.0% and 3.3 +/- 1.7% in PM, and 7.7 +/- 2.7% and 3.9 +/- 1.9% in DM). These differences were statistically significant (P < 0.05) in both sexes for type 1 fibers and in women for type 2 fibers. Also, the average fiber size and hypertrophy factors for type 1 and type 2 fibers were increased in IBM compared to PM and DM. This study confirms that the presence of muscle fiber hypertrophy in biopsies from IBM patients may help differentiate them from other clinically similar inflammatory myopathies.

Dermatomyositis↗
PubMed1992

A chronic myopathy with coated vesicles and tubular masses.

Two muscle biopsies from a 38-yr-old man with a lifelong mild chronic nonprogressive myopathy, showed accumulations of randomly oriented tubules of T-tubular origin, some of which had become greatly dilated and had accumulated osmiophilic material. The tubular masses lacked oxidative enzyme activity but during their evolution acquired esterase and acid phosphatase activity. Tubular areas appeared to break down and lead to intrusions of extracellular space into the center of fibers. Coated vesicles were numerous and often appeared to arise from the tubules. No abnormality could be detected on SDS PAGE electrophoresis of fractions from sucrose gradients.

Adult↗
PubMed1992

Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF).

We investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA(Lys) gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase (COX). The vast majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. The overall proportion of mutant mtDNAs in this population was similar to that in differentiated muscle, suggesting that the ratio of mutant to wild-type mtDNAs in skeletal muscle is determined either in the ovum or during early development and changes little with age. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wild-type clones. The threshold for biochemical expression of the mutation was determined in heteroplasmic myotubes formed by fusion of different proportions of mutant and wild-type myoblasts. The magnitude of the decrease in translation in myotubes containing mutant mtDNAs was protein specific. Complex I and IV subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Approximately 15% wild-type mtDNAs restored translation and COX activity to near normal levels. These results show that the A-to-G substitution in tRNA(Lys) is a functionally recessive mutation that can be rescued by intraorganellar complementation with a small proportion of wild-type mtDNAs and explain the steep threshold for expression of the MERRF clinical phenotype.

Adult↗
PubMed1992

The pathological diagnosis of specific inflammatory myopathies.

Pathological diagnosis of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM) should be possible in almost all cases when an appropriately involved muscle is biopsied. DM shows characteristic patterns of muscle fiber damage and capillary damage. Lymphocytes and macrophages are seen in PM and IBM partially invading non-necrotic fibers. IBM is also characterized by rimmed vacuoles with membranous whorls, characteristic masses of filaments in cytoplasm and sometimes in nuclei, and grouped atrophic fibers. Muscle fiber damage in PM is more variable. Inflammatory myopathy can be associated with HTLV-1 and HIV infection. In the latter a strong resemblance to PM is reported. Separate, still less well characterized forms of inflammatory myopathy occur in young children.

Atrophy↗
PubMed1992

Recent developments in the biology of dystrophin and related molecules.

Important progress in the understanding of various aspects of dystrophin biology continued during the past year. This relates to basic biochemistry, isoforms, subcellular localization in skeletal muscle, regional distribution in brain, physiological role, abnormalities caused by gene mutations and nuclear domain characteristics. Major progress has also taken place in the characterization of the dystrophin-associated glycoprotein (DAG) complex and in the understanding of its role in anchoring dystrophin to the plasmalemma and providing a link to the extracellular matrix. Characterization of the human chromosome-6-related analogue of dystrophin led to the discovery that in Duchenne muscular dystrophy (DMD) this molecule is expressed diffusely at the muscle cell surface and could, in part, compensate for the dystrophin deficiency of DMD.

Animals↗
PubMed1991

Familial inclusion body myositis among Kurdish-Iranian Jews.

We report two cases of adult-onset, slowly progressive limb-girdle muscle weakness with a remarkable sparing of quadriceps muscles that developed in patients from different families of Iranian-Kurdish-Jewish origin. Each patient had a similarly affected sibling. The findings by means of muscle biopsies showed abnormalities typical of inclusion body myositis, including abundant lined vacuoles and characteristic cytoplasmic inclusions of 15- to 18-nm filaments. Remarkably, many vacuolated muscle fibers showed immunoreactivity to neural cell adhesion molecule, a fetal muscle antigen. The common origin of these patients from an isolated ethnic group with frequent consanguinity and the familial incidence is indicative of a genetic causation or predisposition, probably with an autosomal recessive inheritance. This familial myopathy is one of several clinical syndromes that share the typical pathological findings of inclusion body myositis. The pathogenic relationship between these different familial forms and the more common sporadic form of inclusion body myositis is not known.

Adult↗
PubMed1991

In vivo magnetic resonance spectroscopy of brain and muscle in a type of mitochondrial encephalomyopathy (MERRF).

Phosphorus magnetic resonance spectroscopy allows noninvasive measurement of the intracellular phosphate-containing metabolites and intracellular pH in localized volumes of human muscle and brain in vivo. This technique was used to study 8 patients with a mitochondrial cytopathy (myoclonus epilepsy with ragged red fibers). Phosphorus magnetic resonance spectroscopy of resting gastrocnemius muscle demonstrated significantly increased relative intracellular inorganic phosphate concentrations (p less than 0.0005) and decreased phosphocreatine to inorganic phosphate concentration ratios (p less than 0.01) in the patients, although only 3 had myopathic signs or symptoms. We propose, therefore, that phosphorus magnetic resonance spectroscopy of resting skeletal muscle is a useful clinical test in evaluation of progressive myoclonus epilepsy. In contrast to results from muscle, however, the relative phosphate metabolite concentrations and intracellular pH in central volumes of the brains of these patients were normal, despite evidence from our previous positron emission tomography studies suggesting that there is diffuse impairment of cerebral oxidative metabolism.

Brain↗
PubMed1991

Mitochondrial dysfunction in multiple symmetrical lipomatosis.

Multiple symmetrical lipomatosis is a striking clinical finding associated with a variety of peripheral and central nervous system abnormalities. We describe 4 unrelated patients with evidence of mitochondrial dysfunction in skeletal muscle. Multiple symmetrical lipomatosis is an additional, albeit unusual, manifestation of the expanding clinical spectrum of mitochondrial diseases.

Adult↗
PubMed1991

Glucocorticoids and immunosuppressants do not change the prevalence of necrosis and regeneration in mdx skeletal muscles.

Therapeutic doses of methylprednisolone, azathioprine, cyclosporin A, and cyclophosphamide administered to mdx mice between 15 and 45 days of age failed to significantly influence the time course and prevalence of necrosis and regeneration or serum creatine kinase activity. This finding contrasts with previously reported findings of beneficial effects of glucocorticoids in Duchenne muscular dystrophy (DMD). This may indicate that, mechanisms upon which beneficial effects of glucocorticoids depend in DMD, do not operate (sufficiently) in mdx mice.

Animals↗
PubMed1991

Dystrophin is tightly associated with the sarcolemma of mammalian skeletal muscle fibers.

Sarcolemmal vesicles with right-side-out configuration were prepared from normal fresh human and rabbit skeletal muscle bundles by incubation in 140 mM KCl solution containing collagenase. The vesicles were used to examine the association of dystrophin, the protein product of the Duchenne muscular dystrophy gene, with the sarcolemma. Western blot analysis, indirect immunofluorescence, and immunoperoxidase staining using specific antibodies raised against the N-terminal and the C-terminal domains show that dystrophin remains associated with the membrane of sarcolemmal vesicles. Indirect immunofluorescence microscopy using permeabilized and unpermeabilized vesicles indicated that both the N-terminus and the C-terminus of dystrophin are localized to the cytoplasmic surface of the sarcolemma. These results suggest that dystrophin has much stronger attachment to the surface membrane than it has to the internal domain of skeletal muscle fibers. Sarcolemmal vesicles thus represent a new system for studying the function of dystrophin and the molecular basis of its association with the sarcolemma.

Amino Acid Sequence↗
PubMed1991

Major alteration of the pathological phenotype in gamma irradiated mdx soleus muscles.

Two thousand rads of gamma irradiation delivered to the lower legs of ten day old normal and x-chromosome linked muscular dystrophy (mdx) mice caused significant inhibition of tibial bone and soleus muscle fiber growth. In the irradiated mdx solei, there was a major loss of muscle fibers, lack of central nucleation, and some endomysial fibrosis. These features were caused by a failure of regeneration of muscle fibers due to impaired proliferative capacity of satellite cells. Gamma irradiation transforms the late pathological phenotype of mdx muscles, so that in one major aspect (muscle fiber loss) they resemble muscles in Duchenne muscular dystrophy. However, extensive endomysial fibrosis which is another characteristic feature of Duchenne muscular dystrophy did not develop. This experimental model could be useful for the functional investigation of possible beneficial effects of therapeutic interventions in mdx dystrophy.

Animals↗
PubMed1991

In vivo muscle magnetic resonance spectroscopy in the clinical investigation of mitochondrial disease.

We have investigated the sensitivity and specificity of a rapid phosphorus magnetic resonance spectroscopy (MRS) protocol for detecting metabolic abnormalities in vivo in skeletal muscle of patients with mitochondrial disease. We examined 17 patients with mitochondrial myopathies. Sixteen had only mild or minimal myopathic signs and symptoms. Phosphorus magnetic resonance spectra from the resting gastrocnemius muscles showed an abnormal intracellular energy state (marked by an increased intracellular inorganic phosphate concentration) in 14/17. In 3/17, this was associated with a decreased phosphocreatine concentration. We also studied 20 patients with other diseases of muscle (inflammatory myopathies, metabolic myopathies, muscular dystrophies, and myasthenia gravis) that can present with similar clinical features. Spectra showed increased intracellular inorganic phosphate concentrations in 6/20. All of these muscle diseases were associated with evidence of muscle fiber necrosis. Abnormalities in the muscle energy state in these cases may be due to secondary mitochondrial dysfunction. Except for cases of polymyositis and dermatomyositis, these 6 other myopathies could be readily distinguished from the mitochondrial myopathies on the basis of the clinical examination and blood tests. We conclude that phosphorus MRS of resting muscle is practical in a clinical setting and has a useful sensitivity and specificity for mitochondrial myopathies when used in conjunction with standard noninvasive tests.

Adenosine Triphosphate↗
PubMed1991

Inhibition of myosatellite cell proliferation by gamma irradiation does not prevent the age-related increase of the number of dystrophin-positive fibers in soleus muscles of mdx female heterozygote mice.

In skeletal muscles of young mdx female heterozygote mice, there is a mosaic of dystrophin-positive and dystrophin-negative fiber segments. In older animals, there is a marked decline in the number of dystrophin-negative fiber segments. This phenomenon might be due to a fusion of dystrophin-competent satellite cells into the originally dystrophin-negative fiber segments during growth. To study this possibility, soleus muscles of 10-day-old mdx female heterozygotes were gamma irradiated (2000 rads) to inhibit subsequent myosatellite cell proliferation and fusion. In the irradiated soleus muscles of animals at 60 days, the relative amount of dystrophin measured by quantitative immunoblots was not significantly different from that of the contralateral nonirradiated muscles. The prevalence of dystrophin-negative fibers in the 60-day-old irradiated solei was not higher than in the nonirradiated contralateral muscles, implying that dystrophin-competent satellite cell fusion was not a significant factor in the observed conversion. A longitudinal expansion of the cytoplasmic domain of the original dystrophin-competent myonuclei during growth could explain the observed conversion phenomenon.

Aging↗