Endothelial dysfunction in heart failure and potential for reversal by ACE inhibition.
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Angiotensin-Converting Enzyme Inhibitors↗
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Results for “Skeletal muscle dysfunction”
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[Characterization of mitochondrial myopathies through the evaluation of the enzymatic activities involved in energy metabolism].
The activities of the enzymes NADH dehydrogenase, NADH cytochrome e reductase, succinate dehydrogenase, succinate cytochrome e reductase, cytochrome c oxidase and citrate synthase in normal and sick human skeletal muscle mitochondria were determined. A control group was formed by 13 normal people and without using continuous medication. The patient group was formed by 10 people whose pathological diagnosis indicated suspicion of mitochondrial myopathy. A decrease in the activity of the enzymes in all patient was observed: 7 with abnormality in all the tested enzymes; 2 with deficiencies in all the enzymes except cytochrome e oxidase; and 1 with dysfunction only in the activities of succinate dehydrogenase and succinate cytochrome e reductase. The results indicate multiple or combined deficiencies in the respiratory chain, besides dysfunction of citrate synthase in 9 patients. In one exceptional case, the enzymatic deficiency was restricted to complex II. It is possible to conclude that the methodology used herein is adequate and easily applicable to clinical objectives, and that the results obtained allow characterization of the deficient mitochondrial enzymatic complexes, thus showing that the origin of the diseases is an energetic metabolic dysfunction.
Adolescent↗
Endothelial dysfunction in diabetes mellitus.
In the present study, we examined the pattern of Evan's blue (EB) extravasation over time and we verified the effect of two inhibitors of aldose reductase (sorbinil and ARI 509) as well as aminoguanidine, which modulate nitric oxide (NO) production, on streptozotocin-induced capillary extravasation abnormalities in the upper bronchi, heart, kidney, duodenum, pancreas, skeletal muscle and skin. Albumin extravasation was measured using the EB technique (20 mg/kg). On the third day, a transient decrease in EB leakage was observed in the lung (-49%), heart (-29%) and skeletal muscle (-64%). These early changes in EB were transient, and values returned to normal there after. Later on, EB extravasation was significantly enhanced in the skin (+358, +680, +580, +525 and +365, respectively, at 2, 4, 5, 6 and 7 weeks of diabetes), the duodenum (+101, +160, +92, +124 and +76%), the upper bronchus (+70, +113, +70, +41 and +25%) and the pancreas (+43, +102, +46, +15 and +78%). In the kidney, the increase of EB extravasation was significant at 2 weeks (26%), and from 5 to 7 weeks (+12, +22, +36%). The chronic treatment of diabetic rats with aminoguanidine normalized capillary permeability in most tissues, suggesting that NO is involved in the development of endothelium dysfunction in this streptozotocin-induced diabetic model. Treatment with aldose reductase inhibitors selectively normalized EB extravasation in the kidney.
Aldehyde Reductase↗
Local and central sympathetic reflex control of blood flow in skeletal muscle and subcutaneous tissue in normal man.
The effect of age and sex on relative changes in blood flow and vascular resistance in skeletal muscle and subcutaneous tissue during postural changes and during local increase in transmural pressure was studied in 33 healthy subjects. The intra-individual variation was studied in five subjects. Blood flow was measured by the local 133Xenon wash-out method. No relation to age or sex was seen in the centrally elicited sympathetic vasoconstrictor responses in subcutaneous tissue and skeletal muscle and in the locally elicited vasoconstriction in subcutaneous tissue. A small, but statistically significant, correlation to sex and age was found in the local sympathetic vasoconstrictor response in skeletal muscle. The age correlation was caused only by an attenuated response in the young subjects below 40 years of age and may be fortuitous. The intra-individual variation was acceptably small. Based on the present results, a reduction in blood flow in skeletal muscle and subcutaneous tissue during centrally or locally elicited sympathetic vasoconstriction of 10% or less should be considered abnormal. The local 133Xenon wash-out method is of value in examining patients suspected of dysfunction in the sympathetic part of the autonomic nervous system.
Adult↗
Respiratory and limb muscle weakness induced by tumor necrosis factor-alpha: involvement of muscle myofilaments.
The respiratory and limb skeletal muscles become weakened in sepsis, congestive heart failure, and other inflammatory diseases. A potential mediator of muscle weakness is tumor necrosis factor (TNF)-alpha, a cytokine that can stimulate muscle wasting and also can induce contractile dysfunction without overt catabolism. This study addressed the latter process. Murine diaphragm and limb muscle (flexor digitorum brevis [FDB]) preparations were used to determine the relative sensitivities of these muscles to TNF-alpha. Intact muscle fibers were isolated from FDB and microinjected with indo-1 to measure changes in sarcoplasmic calcium regulation. We found that TNF-alpha depressed tetanic force of the diaphragm and FDB to comparable degrees across a range of stimulus frequencies. In isolated muscle fibers, TNF-alpha decreased tetanic force without altering tetanic calcium transients or resting calcium levels. We conclude that (1) TNF-alpha compromises contractile function of diaphragm and limb muscle similarly, and (2) TNF-alpha decreases force by blunting the response of muscle myofilaments to calcium activation.
Actin Cytoskeleton↗
Skeletal muscle deoxygenation during exercise assessed by near-infrared spectroscopy and its relation to expired gas analysis parameters.
The present study was performed to determine the relation between oxygenated hemoglobin (oxy-Hb) changes in working muscles and ventilatory parameters. Six active normal subjects, 21 sedentary normal subjects and 16 patients with heart failure performed an incremental exercise with expired gas analysis. Deoxygenation of the vastus lateralis muscle was monitored for oxy-Hb changes using near-infrared spectroscopy. Near the anaerobic threshold (AT), oxy-Hb started to decrease, forming the first inflection point (P1). Near the respiratory compensation point (RCP), the second inflection point (P2) was observed. Oxygen uptake at the AT, RCP, P1 and P2 decreased in magnitude first in the active normal subjects, then in sedentary normal subjects and finally in the heart failure patients. High correlation was demonstrated between AT and P1 (r=0.8, p<0.0005) and between RCP and P2 (r=0.9, p<0.0005). In 12 sedentary normal subjects who underwent repeat exercise, reproducibility was confirmed for both P1 and P2. Constant work rate exercises were performed in 5 sedentary normal subjects, and in all of them the oxy-Hb remained unchanged below the AT work rate, whereas oxy-Hb decreased above the AT work rate. Exercise capacity, with respect to both working muscle deoxygenation and ventilation, could be evaluated in detail by the concomitant use of near-infrared spectroscopy and expired gas analysis.
Adult↗
[Mitochondrial uncoupling protein as a target of pharmacotherapy for obesity].
Uncoupling protein (UCP) is a transporter family present in the mitochondrial inner membrane, and as its name suggests, it uncouples respiration from ATP synthesis by dissipating the transmembrane proton gradient as heat. UCP is now recognized as a key molecule in metabolic thermogenesis such as cold- and diet-induced heat production, which is a significant component of energy expenditure, and its dysfunction contributes to the development of obesity. Among the UCP family, UCP-1 is expressed exclusively in brown adipose tissue (BAT), while UCP-2 is present in many organs and UCP-3 is in skeletal muscle. BAT thermogenesis by UCP-1, which has been studied most extensively, is controlled directly by sympathetic nerves principally through the beta-adrenergic action of norepinephrine. Since the beta 3-adrenoceptor is present primarily in adipose tissues, its selective agonists stimulate BAT thermogenesis and also lipid mobilization in white adipose tissue without any noticeable effect on beta 1- and beta 2-adrenoceptos. Therefore, beta 3-adrenoceptor agonists would be promising for the pharmacotherapy of obesity. UCP gene expression is up regulated by ligands for nuclear receptors such as thyroid hormone receptor, peroxisome proliferator-activated receptors (PPAR) and retinoid-X receptor. Long chain fatty acids and some of their metabolites are known to activate PPAR and thereby lead to abundant expression of UCP, which may also contribute to increase in energy expenditure and prevention of obesity. The activity of UCP is suppressed by purine nucleotides but activated by fatty acids. Thus, fatty acids increase UCP-mediated thermogenesis by direct activation of UCP and also by increased gene expression, implying some specific fatty acids or their derivatives as an effective anti-obesity tool.
Adrenergic Agonists↗
Mitochondrial disease with chronic progressive external ophthalmoplegia: clinical analysis of 19 cases.
BACKGROUND: Mitochondrial myopathy is the commonest morphological diagnosis in the patients with the syndrome of chronic progressive external ophthalmoplegia. This syndrome consists of a group of clinically heterogeneous disorders. However, systemic analysis on clinical ground is still inexplicably lacking in Chinese. METHODS: Nineteen patients, who fulfilled the following two criteria, were collected and systematically analyzed on clinical ground. 1. Chronic progressive external ophthalmoplegia, characterized by chronic and progressive ptosis and limitation of eyeball movements, was the earliest and dominant clinical syndrome. 2. The mitochondria abnormalities were the only morphological changes on the limb muscle. RESULTS: All patients were clinically classified into three groups. Twelve cases without extra-skeletal involvement were categorized as simple ocular myopathy; 5 cases as ophthalmoplegia plus syndrome because of the associated extra-skeletal dysfunction(s); and 2 cases as Kearns-Sayre syndrome according to the conventional triad (onset before 20 years of age, ophthalmoplegia, pigmentary degeneration of the retina) with at least one of three other major manifestations (heart block, CSF protein over 100 mg/dl, cerebellar syndrome). CONCLUSIONS: The identification of the defects at the DNA level and determination of the phenotypic expression with basic biochemical methods as well as mitochondria DNA analysis are fundamental for more rational classification of mitochondrial myopathy. However, the classification, based on clinical criteria alone, may give the clinicians the convenience in the follow-up management of the non-skeletal disorders for an individual patient. Importantly, some of these disorders are life-threatening but treatable.
Adult↗
Circulatory status and response to cardiac rehabilitation in patients with heart failure.
BACKGROUND: We recently reported that some patients with heart failure and exercise intolerance exhibit severe hemodynamic dysfunction during exercise, whereas others have normal cardiac output responses to exercise. We postulated that patients with preserved cardiac output responses to exercise are limited by deconditioning and would respond to exercise training, whereas patients with reduced cardiac output responses are limited by skeletal muscle underperfusion and would not improve with exercise training. The present study was undertaken to test this hypothesis. METHODS AND RESULTS: Thirty-two patients with heart failure were studied. Hemodynamic response to maximal treadmill exercise was measured; then patients were enrolled in a standard 3-month cardiac rehabilitation program. Peak exercise VO2, lactate threshold, and quality-of-life questionnaires were assessed at 1, 2, and 3 months. Twenty-one patients had normal cardiac output responses to exercise. All 21 patients participated in the rehabilitation program without difficulty, and 9 (43%) responded to rehabilitation, defined as a > 10% increase in both peak exercise VO2 and the anaerobic threshold. Of the 11 patients with reduced cardiac output responses to exercise, 3 discontinued rehabilitation because of severe exhaustion, and only 1 qualified as a responder (9%; P < .04 versus preserved cardiac output). CONCLUSIONS: Patients with heart failure and normal cardiac output responses to exercise frequently improve with exercise training. Patients with severe hemodynamic dysfunction during exercise usually do not improve with training, which suggests that they are limited primarily by circulatory factors.
Blood Circulation↗
Carbohydrate oxidation disorders of skeletal muscle.
PURPOSE OF REVIEW: The major energy sources for muscle contraction are glycogen, glucose and fatty acids, and defects in their oxidative pathways cause metabolic myopathies. Eleven specific enzyme deficiencies of carbohydrate oxidation affect skeletal muscle alone or in combination with other tissues, such as liver, heart or red blood cells. These hereditary glycogen storage diseases cause two major clinical presentations: one characterized by fixed, often progressive muscle weakness, and the other by acute, intermittent, and reversible muscle dysfunction manifesting as exercise intolerance (myalgia on exertion, muscle contractures, myoglobinuria). RECENT FINDINGS: The focus of this review is on recent developments in: clinical features, including a brief description of the newest identified glycogen storage disease type XIII; molecular genetic studies discussing genotype-phenotype correlations in some carbohydrate oxidation disorders; pathophysiological mechanisms, especially those assessed by non-invasive P magnetic resonance spectroscopy; and therapeutic approaches such as nutritional supplementation and gene therapy, including recombinant enzyme replacement. SUMMARY: Although major progress has been made in an understanding of the molecular genetic bases of carbohydrate oxidation defects, the pathophysiology of exercise intolerance and muscle weakness remains to be further clarified. Gene therapy and dietary therapeutic regimes appear promising, but need to be actively investigated in the future.
Animals↗
Peritonitis causes diaphragm weakness in rats.
Respiratory failure is a common and often lethal complication of severe peritonitis. Because this inflammatory process develops in the abdomen, adjacent to the diaphragm, we hypothesized that peritonitis might directly compromise diaphragm function. We tested this hypothesis using male Sprague-Dawley rats. We injected oyster glycogen into the rats' peritoneum, and 16 h later the peritoneum was lavaged for leukocyte analysis and muscle samples were excised. Contractile properties of diaphragm fiber bundles were measured in vitro. We found that neutrophils and macrophages were concentrated in peritoneal lavage fluid of experimental animals (p < 0.01) and were adherent to the abdominal surface of the diaphragm. Immunohistochemistry showed increases in inducible nitric oxide synthase in microvessels of the diaphragm and limb skeletal muscles but not in heart or spleen. Peritonitis decreased maximal force production by the diaphragm (23.6+/-0.6 versus 21.2+/-0.6 N/cm2; p < 0.05) and decreased the absolute forces developed at physiologic stimulus frequencies (> 30 Hz; p < 0.01), depressing the overall force-frequency relationship (p < 0.001). Peritonitis had little effect on acute muscular fatigue. These data demonstrate that peritonitis weakens the diaphragm in rats and suggest that humans with peritonitis may be predisposed to respiratory muscle dysfunction.
Animals↗
Future directions in exercise and immunology: regulation and integration.
Although it is difficult to predict future directions in a rapidly expanding field such as exercise immunology, recently published research along with that presented at this Symposium allow us to ask some key questions which may point to new directions: 1) Are athletes immunocompromised? Athletes are not clinically immunodeficient, yet endurance athletes are at increased risk of illness. Long-term prospective studies are needed to understand the relationship between infection, training variables and immune parameters. 2) Is downregulation of nonspecific immunity beneficial or harmful? In athletes, neutrophils appear to be downregulated, and this may alter resistance to illness. Alternatively, neutrophils are mediators of tissue damage during inflammation. Downregulation of neutrophil function may be protective by limiting chronic inflammation. In athletes, mild immunosuppression may reflect a compromise between the body's attempts to limit inflammation while maintaining immune function. 3) What mediates communication between events in skeletal muscle and the immune system? Leukocyte mobility is affected by metabolic and mechanical factors during exercise. Exercise increases cytokine levels in damaged skeletal muscle and expression of adhesion molecules. Future work is likely to focus on the role of cytokines and adhesion molecules in mediating exercise-induced changes in leukocyte mobility. 4) Can exercise training provide a "countermeasure" against immunosuppressive events? Moderate exercise training may have a role in stimulating the immune system during certain diseases (e.g., HIV-infection), immune dysfunction (e.g., chronic fatigue syndrome) or reduced responsiveness (e.g. aging, spaceflight). It is also likely that future study will apply molecular biology techniques to further identify mechanisms by which exercise influences immune function.
Animals↗
Fiber atrophy and hypertrophy in skeletal muscles of late middle-aged Fischer 344 x Brown Norway F1-hybrid rats.
We examined young adult and late middle-aged male rats to test the hypothesis that gastrocnemius (a locomotor muscle) demonstrates reduced fiber size with aging, whereas soleus (a postural muscle) demonstrates atrophy of some fibers and compensatory hypertrophy in other fibers. Although body mass was greater in late middle-aged animals, mass was reduced in gastrocnemius but not soleus muscle. In another group of animals, physical activity was reduced by 34% in late middle-aged animals. Whereas mean fiber size was lower in gastrocnemius of late middle-aged animals, it was not different in soleus. Histograms revealed atrophied fibers (</=1000 micro m(2)) in soleus and gastrocnemius and hypertrophied fibers (>/=8000 micro m(2)) in soleus with aging. Atrophied fibers often demonstrated no subsarcolemmal mitochondrial staining, suggesting denervation, whereas hypertrophied fibers often demonstrated cytochrome oxidase deficiency, suggesting mitochondrial dysfunction. These results underscore the divergent influences (e.g., physical inactivity, denervation, mitochondrial dysfunction) affecting fiber size with aging.
Aging↗
Computerized calculation of in vitro generation of ATP and creatine phosphate induced by respiration in human muscle mitochondria.
A computer program is presented which calculates the action of adenylate kinase and creatine kinase during the process of adenosine-5'-triphosphate generation by the mitochondria in human skeletal muscle 600 X g supernatants. The results show that the mass action ratios of the two kinase reactions are not influenced by incubation time or decreased rate of oxidative phosphorylation as a result of mitochondrial dysfunction. The program is useful for establishing optimum initial adenosine-5'-diphosphate and creatine concentrations in the assay medium.
Adenosine Triphosphate↗
The role of complementary techniques in managing musculoskeletal pain in performance horses.
The locomotor system requires normal movement for normal function. Movement restrictions of soft tissues and joints stimulate nociceptive pathways in the corresponding vertebral segment. Reflex-induced alterations of sensory and motor neuron activity within the segment lead to detrimental changes within many of the tissues associated with and distant from the area. Manual therapy is utilized in both diagnosis and treatment of tissue and joint movement restrictions. Early recognition and treatment of dysfunction in the equine athlete prevents permanent pathology and facilitates performance excellence.
Animals↗
Variations in levator ani volume and geometry in women: the application of MR based 3D reconstruction in evaluating pelvic floor dysfunction.
OBJECTIVE: We report on the comparative 3-dimensional (3D) living female pelvic floor geometry in five women, comparing the volume, morphology, and integrity of the levator sling, and pelvic anatomic relationships among study subjects. METHODS: Five women of varying ages, parity, continence, and prolapse status were studied. Two-dimensional (2D) imaging of the pelvic floor organs was performed on each subject in the supine position. Manual segmentation techniques and solid modeling software was used to build 3D models of each patient's pelvic floor structures, which could then be viewed and measured on the computer screen. We measured levator muscle volume, posterior urethro-vesical angle, distance from the urethra to pubo-coccygeal line, and the levator plate angle. The integrity of pubo-coccygeal attachments was also recorded. RESULTS: Levator muscle volume ranged from 68 ml in the nulliparous female, to 26 ml in the grand multipara with severe prolapse and mild genuine stress incontinence (GSI). The second lowest volume (30 ml) was in the multipara with GSI. Volumes in the parous subjects without stress urinary incontinence or pelvic organ prolapse were 36 and 39 ml. Pubo-coccygeal attachments were found to be torn in the 2 symptomatic subjects, and were intact in all 3 asymptomatic subjects. CONCLUSION: MR based 3D modeling is feasible and can be used in a research setting to evaluate complex anatomic relationships which may accompany pelvic floor dysfunction. The technique can also be used to evaluate levator muscle morphology and volume, as well as pelvic floor support integrity and its possible role in GSI and prolapse. We are currently conducting a larger study to validate our technique, and to better define the relationship between pelvic floor geometry and pelvic floor dysfunction.
Adult↗
[Etiopathogenesis and pathophysiology of type 2 diabetes].
Etiopathogenesis of type 2 diabetes is complex and still partially unknown. Its etiology is determined by the interaction of genetic and environmental factors. The genetic contribution is important, but has a polygenic origin. Obesity, especially when fat mass is preferably located in the abdomen, is the main predisposing factor for type 2 diabetes, and almost 80% of diabetic patients are overweight or obese. The diabetogenic effect of obesity is due to the capacity of excessive fat mass to induce or aggravate insulin resistance. Increasing lack of physical activity is also a contributing factor as it increases insulin resistance. As far as pathophysiology is concerned, the development of type 2 diabetes results from the coexistence of abnormalities of insulin secretion and insulin action. Insulin secretory dysfunction, whose underlying mechanism remains poorly understood, is characterized by a relative defect in circulating insulin levels of variable severity. Resistance to insulin action is located in the liver (increased hepatic glucose production), in the skeletal muscle (decreased muscular glucose uptake) and in the adipose tissue (exaggerated lipolysis with elevated plasma free fatty acids). Changes in life-style habits (weight reduction, regular physical activity) are able to prevent or delay the development of type 2 diabetes.
Diabetes Mellitus, Type 2↗
The slow skeletal muscle troponin T gene is expressed in developing and diseased human heart.
Cardiac muscle development is characterised by the activation of contractile protein genes and subsequent modulation of expression resulting, ultimately, in the formation of a mature four-chambered organ. Myocardial gene expression is also altered in the adult in response to pathological stimuli and this is thought to contribute to the altered contractile characteristics of the diseased heart. We have examined the expression of the slow skeletal troponin T (TnT) gene in the human heart during development and in disease using whole mount in situ hybridisation and real-time quantitative (TaqMan) polymerase chain reaction (PCR). Slow skeletal TnT mRNA shows transitory and regional expression in the early foetal heart, which occurs at different times in atria and ventricles. In ventricular myocardium, expression is seen in the outer epicardial layer at a time when the coronary circulation is being established. Expression was detected at low levels in the adult human heart and was significantly increased in end-stage heart failure. Similarly, expression was readily detectable during early rat heart development and was up-regulated in pressure overload hypertrophy in adult. Together these data show for the first time that slow skeletal TnT mRNA is readily detectable during early human heart development. They further suggest that slow skeletal TnT may be responsive to myocardial stress and that elevated levels may contribute to myocardial dysfunction in adult disease.
Adult↗