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Results for “Skeletal muscle dysfunction”

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At least 1,207 records · Page 67Linked to original sources

PubMed2004

Leucine acutely reverses burn-induced alterations in translation initiation in heart.

Myocardial dysfunction is a common manifestation of thermal injury, the etiology of which appears to be multifactorial. We have previously demonstrated that burn injury impairs cardiac protein synthesis at the level of translation initiation. The purpose of the present study was to determine whether oral administration of leucine, which is known to stimulate translation initiation in skeletal muscle, can ameliorate burn-induced changes in signal transduction pathways known to regulate protein synthesis in cardiac muscle. To address this aim, thermal injury was produced by a 40% total body surface area full-thickness scald burn in anesthetized rats, and the animals were studied in the fasted condition 24 h later; appropriate time-matched nonburned control rats were also included. Separate groups of control and burn rats also received an oral gavage of leucine. To identify potential mechanisms responsible for regulating mRNA translation in cardiac muscle, several eukaryotic initiation factors (eIFs) were examined using immunoprecipitation and immunoblotting techniques. Hearts from burned rats demonstrated a redistribution of eIF4E as evidenced by the increased binding of the translational repressor 4E-BP1 with eIF4E, a decreased amount of eIF4E bound with eIF4G, and a decreased amount of the hyperphosphorylated gamma-isoform of 4E-BP1. Furthermore, constitutive phosphorylation of mTOR, the ribosomal protein S6, and eIF4G was also decreased in hearts from burned rats. In control rats, leucine failed to alter eIF4E distribution but did increase the phosphorylation of S6K1 and S6. However, in hearts from burn rats, leucine acutely reversed the alterations in eIF4E distribution as well as the changes in S6, eIF4G, and mTOR phosphorylation. These data suggest that oral administration of leucine can acutely reverse multiple defects in cardiac translation initiation produced by thermal injury.

Administration, Oral↗

PubMed1998

Loss of motor units in Alzheimer's disease.

Little attention has been paid in the literature to the state of the peripheral nervous system (PNS) in Alzheimer's disease (AD). We conducted a comprehensive electrophysiological study in 15 AD patients looking for functional abnormalities within their PNSs. A reduction of the number of functioning motor units (MU) was found in the thenar and soleus muscles of most of these patients without enlargement of the remaining MUs territories, while the motor and sensory conduction velocities of the peripheral nerves were preserved. These results suggest dysfunction of the spinal motoneurones in patients afflicted with this condition.

Alzheimer Disease↗

PubMed1999

Functional consequences of a domain 1/S6 segment sodium channel mutation associated with painful congenital myotonia.

An unusual form of painful congenital myotonia is associated with a novel SCN4A mutation causing a valine to methionine substitution in the domain 1/S6 segment of the skeletal muscle sodium channel. We studied the functional characteristics of this mutant allele using a recombinant channel to gain understanding about the nature of the biophysical defect responsible for this unique phenotype. When expressed heterologously in a cultured mammalian cell line (tsA201), the mutant channel exhibits subtle defects in its gating properties similar, but not identical, to other myotonia-producing sodium channel mutations. The main abnormalities are the presence of a small non-inactivating current that occurs during short test depolarizations, a shift in the voltage-dependence of channel activation to more negative potentials, and a slowing of the time course of recovery from inactivation. Flecainide, a potent sodium channel blocker previously reported to benefit patients affected by this form of myotonia, effectively inhibits the abnormal sodium current associated with expression of the mutant channel. Our findings demonstrate the unique pattern of sodium channel dysfunction associated with a D1/S6 myotonia-producing sodium channel mutation, and provide a mechanism for the beneficial effects of flecainide in this setting.

Animals↗

PubMed1997

Clinical and biochemical features of muscle dysfunction in subclinical hypothyroidism.

Alterations in muscle structure and function have been reported in overt hypothyroidism, with decreased activity of enzymes involved in anaerobic and oxidative glucose metabolism. To test whether similar changes in muscle energy metabolism are present in subclinical hypothyroidism (sHT), we studied 12 patients with sHT who complained of mild neuromuscular symptoms. The control group included 10 sex- and age-matched healthy volunteers. Skeletal muscle lactate and pyruvate production were determined in the resting state and during dynamic arm exercise. During exercise, blood lactate was significantly higher in sHT patients than in controls from the third exercise step onward (P = 0.02 at 30%, p = 0.008 at 40%, and P = 0.002 at 50% of maximal voluntary contraction). Moreover, the mean increment in blood lactate during exercise was positively related (r2 = 0.44; P = 0.02) to the duration of sHT, but not to serum levels of TSH, free T3, or free T4. No significant difference was found in blood pyruvate concentrations between the two groups at baseline or during exercise. Thus, the lactate/pyruvate ratio curve paralleled the lactate curve in patients as well as controls. We conclude that muscle energy metabolism is impaired in sHT in rough proportion to the known duration of the disease. Early L-T4 therapy may be useful not only to provide specific treatment for such metabolic changes, but also to avoid progression to frank hypothyroidism.

Adolescent↗

PubMed2005

Gene expression in Huntington's disease skeletal muscle: a potential biomarker.

Huntington's disease (HD) is an incurable and fatal neurodegenerative disorder. Improvements in the objective measurement of HD will lead to more efficient clinical trials and earlier therapeutic intervention. We hypothesized that abnormalities seen in the R6/2 mouse, a greatly accelerated HD model, might highlight subtle phenotypes in other mouse models and human HD. In this paper, we identify common gene expression changes in skeletal muscle from R6/2 mice, Hdh(CAG(150)) homozygous knock-in mice and HD patients. This HD-triggered gene expression phenotype is consistent with the beginnings of a transition from fast-twitch to slow-twitch muscle fiber types. Metabolic adaptations similar to those induced by diabetes or fasting are also present but neither metabolic disorder can explain the full phenotype of HD muscle. The HD-induced gene expression changes reflect disease progression. This raises the possibility that muscle gene expression may be used as an objective biomarker to complement clinical HD-rating systems. Furthermore, an understanding of the molecular basis of muscle dysfunction in HD should provide insight into mechanisms involved in neuronal abnormalities and neurodegeneration.

Animals↗

PubMed2005

Differential proteome analysis of aging in rat skeletal muscle.

To identify the mechanisms underlying muscle aging, we have undertaken a high-resolution differential proteomic analysis of gastrocnemius muscle in young adults, mature adults, and old LOU/c/jall rats. Two-dimensional gel electrophoresis and subsequent MALDI-ToF mass spectrometry analyses led to the identification of 40 differentially expressed proteins. Strikingly, most differences characterized old (30-month) animals, whereas young (7-month) and mature (18-month) adults exhibited similar patterns of expression. Important modifications in contractile (actin, myosin light-chains, troponins-T) and cytoskeletal (desmin, tubulin) proteins, and in essential regulatory proteins (gelsolin, myosin binding proteins, CapZ-beta, P23), likely account for dysfunctions in old muscle force generation and speed of contraction. Other features support decreases in cytosolic (triose-phosphate isomerase, enolase, glycerol-3-P dehydrogenase, creatine kinase) and mitochondrial (isocitrate dehydrogenase, cytochrome-c oxidase) energy metabolisms. Muscle aging is often associated with increased oxidative stress. Accordingly, we observed differential regulation of molecular chaperones (hsp20, hsp27, reticuloplasmin ER60) and of proteins implicated in reactive aldehyde detoxification (aldehyde dehydrogenase, glutathione transferase, glyoxalase). We further noticed up-regulation of proteins involved in transcriptional elongation (RNA capping protein) and RNA-editing (Apobec2). Most of these proteins were previously unrecognized as differentially expressed in old muscles, and they represent novel starting points for elucidating the mechanisms of muscle aging.

Aging↗

PubMed1999

Altered expression of myosin heavy chain in the vastus lateralis muscle in patients with COPD.

This study was designed to further characterize peripheral skeletal muscle alterations in patients with chronic obstructive pulmonary disease (COPD) and to evaluate the possible relationship between myosin heavy chain (MyoHC) isoform expression and exercise tolerance in these individuals. MyoHC composition from biopsy of the vastus lateralis muscle was examined in 12 COPD patients (forced expiratory volume in one second (FEV1)=31+/-9% predicted, peak oxygen consumption (V'O2)=15+/-4 mL x kg(-1) x min(-1)) and 10 age-matched normal male subjects (peak V'O2=20+/-5 mL x kg(-1) x min(-1)). The proportion of MyoHC type I was smaller in COPD than in normals (27+/-17% versus 41+/-9%, p<0.05) with an increase in MyoHC type IIa (51+/-15% versus 39+/-9%, p<0.05) and the proportion of MyoHC type IIx being comparable between both groups. A significant relationship was found between peak V'Oo2 mL x kg(-1) x min(-1) and FEV1 % pred (r=0.91, p<0.0001) and the percentage of MyoHC type I (r=0.61, p=0.016). In stepwise multiple regression, only FEV1 % pred was found to be a significant determinant of peak V'O2 (p<0.0001). This variable explained 83% of the total variance of peak V'O2. In summary, this study showed considerable modifications in the phenotypic expression of the myosin heavy chain in the vastus lateralis muscle in patients with chronic obstructive pulmonary disease. An independent effect of myosin heavy chain expression on exercise capacity was not found. These results suggest that chronic inactivity and muscle deconditioning may not be the sole factors explaining peripheral muscle dysfunction in patients with chronic obstructive pulmonary disease.

Aged↗

PubMed2004

Vasomotor dysfunction after cardiac surgery.

Cardiopulmonary bypass and cardioplegic arrest, which allow for support of the circulation and stabilization of the heart during cardiac procedures, are still used for the vast majority of cardiac operations worldwide. However, in addition to a well-recognized systemic inflammatory response, cardiopulmonary bypass and cardioplegic arrest elicit complex, multifactorial vasomotor disturbances that vary according to the affected organ bed, with reduced vascular resistances in the skeletal muscle and peripheral circulation, and increased propensity to spasm in the cardiac, pulmonary, mesenteric and cerebral vascular beds. This article outlines the nature, mechanistic basis, and clinical correlates of the vasomotor alterations encountered in patients undergoing cardiac surgery using cardiopulmonary bypass and cardioplegic arrest.

Cardiopulmonary Bypass↗

PubMed2006

Immunohistochemical and ultrastructural abnormalities in muscle from a patient with sensorineural hearing loss related to a 1555 A-to-G mitochondrial mutation.

Genetic studies indicate that hereditary susceptibility of the inner ear to aminoglycoside antibiotic toxicity is caused by a nucleotide 1555 A-to-G mutation in the mitochondrial 12S rRNA gene. Although the phenotype associated with this mutation is nonsyndromic hearing loss, the possibility remains that there could be effects on other tissues that, like the inner ear, contain numerous mitochondria, particularly muscle. We obtained a temporalis muscle specimen from a deaf patient with the A1555G mutation and found informative pathologic features, including mosaic activity of cytochrome c oxidase immunoreactivity and mitochondrial ultrastructure. These findings suggest that mitochondrial dysfunction from the A1555G mutation extends beyond the inner ear.

Electron Transport Complex IV↗

PubMed2001

Excitatory and inhibitory mechanisms in Wilson's disease: investigation with magnetic motor cortex stimulation.

We have evaluated cortical excitability in nine patients affected by Wilson's disease (WD) using transcranial magnetic (TMS) and electric (TES) cortical stimulation and central silent period (CSP) data. A clinical score was derived from the sum of scores assigned to extrapyramidal, pyramidal and cerebellar signs. All patients underwent TMS. Motor evoked potentials (MEPs) from abductor pollicis brevis (APB) and tibialis anterior (TA) muscles were recorded. MEP threshold and amplitude, central motor conduction time (CMCT), CSP threshold, CSP and peripheral silent period (PSP) duration were measured. Three patients also underwent transcranial bifocal electric cortical stimulation (TES) and MEPs were recorded from the APB muscle, and CMCT, MEP threshold and amplitude were measured. TMS MEPs were absent from relaxed muscles in six patients and from contracted muscles in three. CMCT was prolonged in six patients. APB CMCT correlated with clinical score. In three patients in whom TMS revealed abnormal or no MEP, TES MEPs were of normal threshold and amplitude. The CSP threshold was increased in seven patients, and CSP was absent in one. These results suggest an intracortical presynaptic motor dysfunction in WD.

Adult↗

PubMed1996

Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.

The muscle myosins and hexomeric proteins consisting of two heavy chains and two pairs of light chains, the latter called essential (ELC) and regulatory (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Their function in striated muscle, however, is only partially understood. We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle. We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three-dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles.

Amino Acid Sequence↗

PubMed2001

Hepatocyte growth factor ameliorates acute graft-versus-host disease and promotes hematopoietic function.

Acute graft-versus-host disease (GVHD) is a major complication of bone marrow transplantation (BMT) and is characterized by hematopoietic dysfunction, immunosuppression, and tissue injury in the skin, liver, and intestinal mucosa. Hepatocyte growth factor (HGF), originally identified and cloned as a potent mitogen for hepatocytes, induces mitogenic and antiapoptotic activity in various epithelial cells and promotes hematopoiesis. Working in a murine model of acute GVHD, we performed repeated transfection of the human HGF cDNA into skeletal muscle and showed that this treatment inhibited apoptosis of intestinal epithelial cells and donor T-cell infiltration into the liver, thereby ameliorating the enteropathy and liver injury caused by acute GVHD. HGF also markedly suppressed IFN-gamma and TNF-alpha expression in the intestine and liver and decreased the serum IL-12. Furthermore, extramedullary hematopoiesis by donor cells was increased, and the survival rate was improved. These results suggest that HGF may be useful for controlling acute GVHD after allogeneic BMT.

Animals↗

PubMed1994

Biochemical and molecular studies of mitochondrial function in diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

OBJECTIVE: To determine if diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) combined with a cerebellar syndrome is associated with a systemic disorder of respiratory chain function as found in similar genetic syndromes. CASE: A muscle biopsy was taken from a patient with DIDMOAD, and a mitochondrial fraction was prepared. Respiratory chain function was assessed by analysis of intermediary metabolites, histochemical analysis of muscle biopsy, measurement of the activity of individual respiratory chain complexes, oxidative flux through the respiratory chain, and cytochrome concentration and compared with a population with normal respiratory chain function. Mitochondrial DNA from skeletal muscle, brain, and pancreas was examined for major rearrangements and specific point mutations. Brain tissue was examined neuropathologically for abnormalities, particularly those previously described in association with DIDMOAD. RESULTS: No abnormality was found in mitochondrial oxidation, individual complex activity, or cytochrome concentration. Histochemical analysis and electron microscopy showed no abnormality known to be associated with mitochondrial dysfunction. A single-base substitution at position 12308 of the mitochondrial genome was found, but no major rearrangement of mitochondrial DNA was demonstrated. Neuropathological examination revealed severe demyelination and gliosis in the optic nerves and loss of Purkinje cells associated with gliosis in the white matter in the cerebellum. CONCLUSIONS: We have found no evidence that DIDMOAD is associated with a systemic abnormality of respiratory chain function. The mitochondrial DNA single-base substitution noted is likely to be a polymorphism rather than a pathogenic point mutation. We have confirmed that DIDMOAD may be associated with a neurodegenerative disorder, but the cause of this remains undetermined.

Adult↗

PubMed1999

Angiotensin-converting enzyme inhibitors and end-organ damage in heart failure.

Angiotensin-converting enzyme (ACE) inhibitors play an important role in protecting various organs in patients with congestive heart failure. The mechanisms of action of ACE inhibitors in congestive heart failure are multiple and may involve important effects on endothelial function in addition to the well known hemodynamic and neurohormonal effects. Skeletal muscle fatigue can play an important role in the pathophysiology of congestive heart failure, and only aggressive treatment with ACE inhibitors and exercise training can improve exercise tolerance and reduce the risk of further deterioration of cardiac function. ACE inhibitors should be introduced with caution in patients with severe heart failure and hypotension to prevent renal dysfunction. Unlike some other ACE inhibitors, perindopril seems to cause no first dose hypotension. It also appears to have a neutral effect on renal function in patients with severe congestive heart failure.

Journal Article↗

PubMed1999

Angiotensin-converting enzyme inhibitors and end-organ damage in heart failure.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Mitochondrial energy metabolism in brain-dead organ donors.

OBJECTIVES: Change from aerobic to anaerobic metabolism has been described in brain-dead organ donors (BDOD) managed for organ procurement. Such modifications could lead to a depletion in intracellular adenine nucleotides and in part explain primary graft dysfunction. The purpose of this study was to investigate the mitochondrial energy metabolism in BDOD using permeabilized muscle fibers. METHODS: With institutional approval, the study was performed prospectively in 15 consecutive BDOD. In each patient, muscle biopsy and blood samples for the determination of plasma lactate and pyruvate were obtained just before organ removal. Mitochondrial respiratory parameters of skeletal muscle were determined in saponin-skinned muscle fibers. Mitochondrial oxygen consumption rates were measured polarographically using different substrates and inhibitors of the respiratory chain complexes. Results were compared to those obtained from muscle biopsies performed in 10 healthy patients during orthopedic surgery. RESULTS: Fifteen donors, 13 men and 2 women, aged 35 +/- 11 yrs, were studied. All patients had a high lactate-to-pyruvate ratio (10). Mitochondrial respiration rates were significantly decreased during adenosine triphosphate (ATP) synthesis. CONCLUSIONS: Major changes in energy metabolism occurred during brain death with a decrease in ATP synthesis capacity. High-risk donors should be recognized for a better graft evaluation.

Adenosine Triphosphate↗

PubMed1975

Cellular potassium transport and ATPase activity in Bartter's syndrome.

The cellular membrane function expressed as ATPase activity and active cellular K+ changes during in vitro incubation has been studied in two siblings with Bartter's syndrome. The K+ content of skeletal muscle was 20% lower than for controls, and the active potassium transport ability of single skeletal muscle cells was also lower than that of controls. The total ATPase activity of red cell membranes was higher, but the ratio of Na+-K+-activated to Mg2+-activated ATPases was lower than for control patients. The results favour the hypothesis that a primary defect causing the Bartter's syndrome could be an inherited generalized membrane dysfunction in the handling of cations.

Adenosine Triphosphatases↗

PubMed1998

[Genetics of dilated cardiomyopathy].

Dilated cardiomyopathy (DCM) is a heart muscle disorder characterized by cardiac dilatation and impaired systolic function. In an increasing number of all DCM cases a specific etiology can be identified and in the remaining patients DCM is termed idiopathic. There is a wide variation of the clinical presentation in DCM. The majority of patients manifests classical disease, i.e. heart failure due to left (and right) ventricular systolic dysfunction. However, some cases may come to clinical attention because of supraventricular arrhythmias such as sinus node dysfunction, AV-block or atrial fibrillation. Although a multitude of etiologies may be responsible for DCM (e.g. viral, immunological, toxic), the disease is inherited as a single gene disorder in at least 20 to 35% of cases. Most genetic forms of DCM are caused by autosomal dominant gene defects. Six dominant disease loci on chromosomes 1p1-q1, 1q32, 3p22-p25, 6q23, 9q13 und 10q21-q23 have been identified but the corresponding disease genes are not yet known. X-linked DCM without skeletal muscle disease is a rare variety of adult DCM which can be caused by specific mutations in the dystrophin gene on chromosome Xp21.

Adult↗