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PubMed2000

Interaction between L-type Ca2+ channels and sarcoplasmic reticulum in the regulation of vascular tone in isolated rat small arteries.

A dysfunction of the sarcoplasmic reticulum (SR) causes an increase in the myogenic tone of rat skeletal muscle small arteries (A(SK)), but not that of mesenteric small arteries (A(MS)). We hypothesized that the difference depends on the activity of voltage-dependent Ca2+ channels in these vessels. To test this, we measured the membrane potential of these vessels and examined ryanodine-induced constrictions by manipulating the activity of voltage-dependent Ca2+ channels. The isolated vessels were cannulated to control the transmural pressure. To assess the vascular tone, the inner diameter was measured with a video-digitizing system. The membrane potential of A(SK) was more depolarized between 20 to 100 mm Hg of transmural pressure. A(MS) was not constricted by the Ca2+ channel agonist Bay K 8644 (1 nM(-1) microM) alone, but substantially constricted in the presence of ryanodine (1 microM). Ryanodine also augmented the KCl (20 mM)-induced constriction. In A(SK), the Ca2+ channel blocker nisoldipine fully dilated the ryanodine-induced constriction: however, the ryanodine-induced constriction was less susceptible to nisoldipine than was the myogenic and phenylephrine-induced constriction caused mainly by increased Ca2+ influx. In conclusion, the contribution of the SR function to Ca2+ metabolism depends on the activity of dihydropyridine-sensitive Ca2+ channels. The dysfunction of SR by ryanodine may impair the Ca2+ extrusion rather than increase Ca2+ influx in rat small arteries.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2004

Gene expression in the pathophysiology of type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta-cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. With recent advances in genomic techniques, it is now possible to assess gene expression patterns in small samples of muscle tissue from metabolically characterized humans. We have applied these techniques to identify genes and pathways potentially important in the pathogenesis of DM. Both DM and the insulin resistance characteristic of "prediabetes" are associated with reduced expression of genes encoding key enzymes in oxidative metabolism and mitochondrial function, and highlight the potential central role for oxidative metabolic pathways in the pathogenesis of type 2 DM.

Animals↗

PubMed1999

Resting muscle sympathetic nerve activity and peak oxygen uptake in heart failure and normal subjects.

AIMS: Exercise intolerance and increased efferent vasoconstrictor traffic to muscle are two characteristics of heart failure that have not been explicitly linked. We tested the hypothesis that peak oxygen consumption is inversely related to resting muscle sympathetic nerve activity in heart failure. METHODS AND RESULTS: We recorded peroneal muscle sympathetic nerve activity in 17 treated heart failure patients (16 men,1 woman; mean ejection fraction of 26. 0+/-3.2% (SE)) and 17 age-matched healthy subjects (16 men, 1 woman). Oxygen consumption was measured during cycle ergometry to maximal effort. In heart failure and normal subjects, mean peak oxygen consumption was 20.6+/-1.7 vs 32.2+/-2.6 ml x kg-1 x min-1(P<0.0001) and mean muscle sympathetic activity was 49.3+/-2.8 vs 33.0+/-3.3 bursts x min-1(P<.0007) respectively. When age was accounted for by multiple regression analysis, there was a significant relationship between peak oxygen consumption and burst frequency in heart failure (P<0.02) but not in healthy subjects. The percent of predicted peak oxygen consumption achieved (based on age, sex and body size) was inversely related to muscle sympathetic nerve burst frequency in heart failure (r=-0.71, P<0.0014) but not in normal subjects (r=-0. 44, P<0.08;P<0.0001 for this comparison). CONCLUSION: Reduced exercise capacity in heart failure is related to increased efferent sympathetic traffic to calf muscle. These observations are consistent with the concept of a peripheral neurogenic limit to exercise in heart failure.

Adult↗

PubMed2003

Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.

Type 2 diabetes mellitus (DM) is characterized by insulin resistance and pancreatic beta cell dysfunction. In high-risk subjects, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, glycogen synthesis, and accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and DM has been identified in humans. To identify genes potentially important in the pathogenesis of DM, we analyzed gene expression in skeletal muscle from healthy metabolically characterized nondiabetic (family history negative and positive for DM) and diabetic Mexican-American subjects. We demonstrate that insulin resistance and DM associate with reduced expression of multiple nuclear respiratory factor-1 (NRF-1)-dependent genes encoding key enzymes in oxidative metabolism and mitochondrial function. Although NRF-1 expression is decreased only in diabetic subjects, expression of both PPAR gamma coactivator 1-alpha and-beta (PGC1-alpha/PPARGC1 and PGC1-beta/PERC), coactivators of NRF-1 and PPAR gamma-dependent transcription, is decreased in both diabetic subjects and family history-positive nondiabetic subjects. Decreased PGC1 expression may be responsible for decreased expression of NRF-dependent genes, leading to the metabolic disturbances characteristic of insulin resistance and DM.

Adult↗

PubMed2005

Cardiomyopathy in dystrophin-deficient hearts is prevented by expression of a neuronal nitric oxide synthase transgene in the myocardium.

Null mutation of dystrophin causes the lethal pathology of Duchenne muscular dystrophy (DMD) in which there is progressive pathology of skeletal and cardiac muscles. A large proportion of DMD patient deaths are attributable to cardiac dysfunction associated with ventricular fibrosis, arrhythmias and conduction abnormalities, although the relationships between the dystrophin mutation and the cardiac defects are unknown. Here, we tested whether cardiac pathology in dystrophin-deficient mdx mice can be corrected by the elevated production of nitric oxide (NO) by the myocardium. Dystrophin-deficient mdx mice were produced in which there was myocardial expression of a neuronal nitric oxide synthase (nNOS) transgene. Expression of the transgene prevented the progressive ventricular fibrosis of mdx mice and greatly reduced myocarditis. Electrocardiographs (ECG) attained by radiotelemetry of freely ambulatory mice showed that mdx mice displayed cardiac abnormalities that are characteristic of DMD patients, including deep Q-waves, diminished S:R ratios, polyphasic R-waves and frequent premature ventricular contractions. All of these ECG abnormalities in mdx mice were improved or corrected by nNOS transgene expression. In addition, defects in mdx cardiac autonomic function, which were reflected by decreased heart rate variability, were significantly reduced by nNOS transgene expression. These findings indicate that increasing NO production by dystrophic hearts may have therapeutic value.

Animals↗

PubMed2002

Glucose and reactive oxygen species.

PURPOSE OF REVIEW: This review aims at presenting new concepts of glucose-induced damage in diabetes via an increased production of oxygen free radicals. RECENT FINDINGS: Reactive oxygen species modulate various biological functions by stimulating transduction signals, some of which are involved in diabetes pathogenesis and complications. SUMMARY: Diabetes is characterized by high glucose concentrations that lead, via several mechanisms (glucose autoxidation, stimulation of the polyol pathway, activation of the reduced form of nicotinamide adenine dinucleotide phosphate oxidase, and production of advanced glycation endproducts), to an increased production of reactive oxygen species. The resulting oxidative stress (the imbalance between reactive oxygen species production and the antioxidant defences) can play a key role in diabetes pathogenesis. Superoxide radicals generated by the reduced form of nicotinamide adenine dinucleotide phosphate oxidase may thus contribute to impaired endothelium-dependent vascular relaxation by the inactivation of nitric oxide, and more generally to vascular dysfunction, thereby contributing to accelerated atherosclerosis in diabetic patients. The increased production of reactive oxygen species induced by hyperglycaemia has also been suggested to be involved in platelet dysfunction, in tissue remodelling (via metalloproteinases), and in redox regulation of glucose transport in skeletal muscle. Beyond the classic treatments for diabetes, new therapeutic strategies involving antioxidants or anti-advanced glycation endproduct molecules are proposed. Future methods could take into account the signalling pathways and genes that are regulated by reactive oxygen species.

Antioxidants↗

PubMedDate not supplied

Exercise as a treatment modality for congestive heart failure.

Chronic congestive heart failure is a clinical syndrome that affects nearly 5 million people in the United States alone. Patients with this condition have symptoms of dyspnea and exertional fatigue that often limit their daily activities and decrease their quality of life. There has recently been a paradigm shift in the management of congestive heart failure. Current strategies are focusing on improving the central cardiopulmonary abnormalities, such as decreased ejection fraction and increased capillary wedge pressure, and interventions aimed at improving the numerous peripheral changes that occur with congestive heart failure. Exercise as a treatment modality has been shown to affect many of these peripheral changes, specifically abnormalities in the skeletal muscle, peripheral blood flow, and neurohormonal milieu, which improve with appropriate exercise regimes. Exercise also reduces the symptoms of exertional fatigue, improves quality of life, and increases survival. This article reviews the current experience with exercise and congestive heart failure and discusses strategies used to implement an exercise program for patients.

American Heart Association↗

PubMed2004

Gene expression in humans with diabetes and prediabetes: what have we learned about diabetes pathophysiology?

PURPOSE OF REVIEW: Type 2 diabetes mellitus is characterized by insulin resistance and pancreatic beta-cell dysfunction. In high-risk individuals, the earliest detectable abnormality is insulin resistance in skeletal muscle. Impaired insulin-mediated signaling, gene expression, and glycogen synthesis, and the accumulation of intramyocellular triglycerides have all been linked with insulin resistance, but no specific defect responsible for insulin resistance and diabetes mellitus has been identified in humans. However, recent analyses of gene expression patterns in muscle tissue from metabolically characterized humans have highlighted new genes and pathways potentially important in the pathogenesis of diabetes mellitus. This review will summarize these data and highlight the potential importance of oxidative metabolism in diabetes pathophysiology. RECENT FINDINGS: Genomic analysis of skeletal muscle samples from patients with diabetes mellitus has revealed the reduced expression of genes encoding key enzymes in oxidative metabolism and mitochondrial function. Moreover, the same pattern of gene expression is also observed in insulin resistant 'prediabetic' individuals with normal glucose tolerance. Many of the genes dysregulated in both diabetes and 'prediabetes' are regulated by the transcription factor nuclear respiratory factor-1 and the peroxisome proliferator-activated receptor gamma co-activator 1. These data suggest a potential role for both genetic and environmental factors to modify the risk of diabetes by modifying the expression or activity of these transcriptional regulators. SUMMARY: Nuclear respiratory factor and peroxisome proliferator activated receptor gamma co-activator-1-dependent oxidative metabolic pathways may play a central, and potentially primary, role in the pathogenesis of type 2 diabetes. Additional studies will be required to identify upstream genetic and environmental determinants of this expression phenotype.

Diabetes Mellitus, Type 2↗

PubMed2005

Pelvic floor exercises for erectile dysfunction.

OBJECTIVE: To examine the role of pelvic floor exercises as a way of restoring erectile function in men with erectile dysfunction. PATIENTS AND METHODS: In all, 55 men aged > 20 years who had experienced erectile dysfunction for > or = 6 months were recruited for a randomized controlled study with a cross-over arm. The men were treated with either pelvic floor muscle exercises (taught by a physiotherapist) with biofeedback and lifestyle changes (intervention group) or they were advised on lifestyle changes only (control group). Control patients who did not respond after 3 months were treated with the intervention. All men were given home exercises for a further 3 months. Outcomes were measured using the International Index of Erectile Function (IIEF), anal pressure measurements and independent (blinded) assessments. RESULTS: After 3 months, the erectile function of men in the intervention group was significantly better than in the control group (P < 0.001). Control patients who were given the intervention also significantly improved 3 months later (P < 0.001). After 6 months, blind assessment showed that 40% of men had regained normal erectile function, 35.5% improved but 24.5% failed to improve. CONCLUSION: This study suggests that pelvic floor exercises should be considered as a first-line approach for men seeking long-term resolution of their erectile dysfunction.

Adult↗

PubMed2006

Heart failure attenuates muscle metaboreflex control of ventricular contractility during dynamic exercise.

Underperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex (MMR). In normal dogs during mild exercise, MMR activation causes large increases in cardiac output (CO) and mean arterial pressure (MAP); however, in heart failure (HF) although MAP increases, the rise in CO is virtually abolished, which may be due to an impaired ability to increase left ventricular contractility (LVC). The objective of the present study was to determine whether the increases in LVC seen with MMR activation during dynamic exercise in normal animals are abolished in HF. Conscious dogs were chronically instrumented to measure CO, MAP, and left ventricular (LV) pressure and volume. LVC was calculated from pressure-volume loop analysis [LV maximal elastance (E(max)) and preload-recruitable stroke work (PRSW)] at rest and during mild and moderate exercise under free-flow conditions and with MMR activation (via partial occlusion of hindlimb blood flow) before and after rapid ventricular pacing-induced HF. In control experiments, MMR activation at both workloads [mild exercise (3.2 km/h) and moderate exercise (6.4 km/h at 10% grade)] significantly increased CO, E(max), and PRSW. In contrast, after HF was induced, CO, E(max), and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, E(max) and PRSW did not change. In addition, MMR activation caused no significant change in CO, E(max), or PRSW at either workload. We conclude that MMR causes large increases in LVC in normal animals but that this ability is abolished in HF.

Animals↗

PubMed2006

Recognition and activation of ryanodine receptors by purines.

Ryanodine receptor (RyR) is a tetrameric, high molecular weight protein that functions as a calcium release channel. It plays a key role in phenomena such as signal transduction, excitation-contraction and excitation-secretion coupling. Hyperthermia maligna, central core disease and myocardial infarction have been related with RyR dysfunction. RyR is present as three isoforms in vertebrates: RyR 1 mainly localized in skeletal muscle, RyR 2 in cardiac muscle, and RyR 3 in nervous system. RyR is regulated by a number of physiological and pharmacological factors. Main physiological modulators: calcium, kinases and phosphatases, redox state and energy charge. Main pharmacological regulators: caffeine, dantrolene, ruthenium red, heavy metals and ryanodine. Purines have to do with both, physiological and pharmacological regulation of the RyR activity. So far, the mechanisms of RyR activation by ATP and caffeine have been described in detail using [3H]-ryanodine binding assays and unitary channel activity recorded in planar lipid bilayers. However, some questions remain to be addressed and are at present aim of active scrutiny: How many sites for purines are present in the RyR? Is the same site recognized by nucleotides and methylxanthines? What differences exist among the interaction between RyR and purine bases, nucleosides and nucleotides? Are the phosphate groups important for the recognition of nucleotides? Is the sugar moiety important for the recognition of nucleosides? The review article will examine the most recent specialized literature about the mechanism of activation of RyR by purines with emphasis on reports with approaches of structure-function and structure-activation.

Animals↗

PubMed2001

Cardiac troponin T and creatine kinase MB are not increased in exterior oblique muscle of patients with renal failure.

BACKGROUND: Serum cardiac troponin T (cTnT) concentrations may be increased in patients with renal dysfunction without evidence of cardiac damage, as assessed by conventional methods. It has been suggested that these positive measurements result from the expression in skeletal muscle of fetal isoforms of cTnT, which are detected by the cTnT immunoassay. METHODS: Skeletal muscle (exterior oblique) biopsies were taken from healthy living kidney donors (n = 5) and transplant recipients (n = 19). The amounts of cTnT and creatine kinase (CK) isoenzymes in skeletal muscle of healthy controls were compared with those in patients with renal failure (Wilcoxon-Mann-Whitney test). cTnT was measured quantitatively by a second-generation assay, with a limit of detection of 1 microg/g of protein, and qualitatively by immunohistochemistry and immunoblotting. CK-MB was measured by quantitative electrophoresis. RESULTS: Minute quantities of cTnT were detected in 2 of the 5 (40%) control samples and 9 of the 19 (47%) renal failure samples, respectively, at mean concentrations of <5 microg/g of protein for both subject groups. This was <1/6000th that found in heart muscle. There was no significant difference in cTnT or CK-MB content in skeletal muscle between healthy controls and patients with renal failure. Increased serum cTnT did not predict detectable cTnT in skeletal muscle. cTnT was not detected qualitatively by immunoblotting or immunohistochemistry in any skeletal muscle samples. CONCLUSIONS: Uremia does not affect the content of cTnT or CK-MB in exterior oblique muscle, suggesting that cTnT detected in serum from patients with renal failure does not originate from skeletal muscle.

Adult↗

PubMed1991

[HTLV-I associated myelopathy (HAM) and sarcoid myopathy].

A 65-year-old house-wife developed dirty erythematous rash on her face in April, 1989. Almost simultaneously, she complained of muscle soreness and weakness on both lower extremities. Pathological findings of the skin biopsy at that time was consistent with those of sarcoidosis with moderate inflammatory cell infiltration. In December, 1989, when she was admitted to our hospital, her lower extremities were paretic with marked spasticity, and mild bladder dysfunction was noted. HTLV-I antibody titers in serum and cerebrospinal fluid were significantly elevated. Biopsied limb skeletal muscle revealed the findings of the sarcoid myopathy with small inflammatory cell infiltration in endomysium. HLA haplotypes showed A24, B7, BW61, CW7, CW8, DR1 and DR4 which show relatively common types of those in HAM. Corticosteroid treatments including the methylprednisolone pulse therapy healed the skin lesion, but did not improve her neurological signs. Paraplegia and urinary disturbance were progressive. It is concluded that the inflammatory sarcoid myopathy with HAM in this patient may be caused by a common abnormal immunological background.

Aged↗

PubMed1998

Spontaneous thymoma rat as a model for myasthenic weakness caused by anti-ryanodine receptor antibodies.

The mechanism of muscle weakness in myasthenia gravis and its possible relation to antibodies that are directed against the ryanodine receptor (RyR) were studied by the use of the spontaneous thymoma rat (Buffalo/Mna strain). The present study focused on the motor dysfunction as complicated by impaired subcellular machineries and noted particularly in patients with thymus abnormalities. Rats began to develop skeletal muscle weakness soon after birth and worsened progressively. Rats aged 3 months showed a benign thymoma characterized by proliferative lymphocytes; epithelial cells were stained with anti-RyR peptide antibody. The rat serum contained anti-RyR antibodies, but no anti-acetylcholine receptor antibodies. The electrophysiological study in muscle showed a reduction of contractile force without abnormality in synaptic transmission and membrane properties, suggesting a defect in excitation-contraction coupling. Hypothetically, thymic epithelial cells and skeletal muscles share a common RyR antigen, so that anti-RyR antibodies that target the thymic tissue may react with a homologous target in the muscle.

Animals↗

PubMed2002

Apoptosis and oncosis in the early progression of left ventricular dysfunction in the cardiomyopathic hamster.

The genetic defect in the cardiomyopathic (CM) hamster is a mutation in the glycoprotein-sarcoglycan (a component of the dystrophin-glycoprotein complex). Apoptosis has been identified in skeletal muscle of dystrophin-deficient mice, and therefore the role of myocardial apoptosis in relation to oncosis in causing myocardial necrosis was assessed at the onset of left ventricular (LV) dysfunction in CM hamsters. LV size and function were evaluated in normal and CM hamsters (CHF147 line) by echocardiography at 1, 2, 3, and 5 months (mo) of age. The decrease of LV fractional shortening was found to be most marked (45%) between 1 and 2 mo of age. Apop totic nuclei were identified at each time point using in situ end-labeling of DNA strand breaks (TUNEL), together with immunolabeling of myocytes; DNA fragmentation (laddering) and nuclear morphology were also assessed. Myocyte oncotic necrosis was assessed at 2 mo by Evans blue dye (EBD), wheat germ agglutinin, hematoxylin/eosin staining, and electron microscopy. Apoptotic nuclei were not detected in age-matched normal hamsters. In the CM hamsters apoptotic myocyte nuclei comprised an average of 0.041% of myocyte nuclei between 1 and 5 mo, an increase at 2 mo (to 0.076%) was not significant, and DNA laddering was not detected. The number of myocyte nuclei per unit area decreased by 32% between 1 and 2 mo, and in 2 mo old CM hamsters myocardial staining with EBD was positive in 9.82% of the myocardial cross sectional areas examined, most of which was consistent with sarcolemmal rupture and oncosis with inflammatory cell infiltration. It is concluded that myocyte oncosis provides the major mechanism for the decreased number of myocyte nuclei and the early decrease of cardiac function between 1 and 2 mo of age in the CM hamster, with only a small contribution of myocyte apoptosis.

Animals↗

PubMed2003

Mitochondrial dysfunction and apoptosis in myopathic mice with collagen VI deficiency.

Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col6a1-/-) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1-/- muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1-/- mice on incubation with the selective F1F(O)-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca2+ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1-/- myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1-/- mice with CsA rescued the muscle ultrastructural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.

Animals↗

PubMed2002

The role of mitochondrial nitric oxide synthase in inflammation and septic shock.

Nitric oxide and cytokines constitute the molecular markers and the intercellular messengers of inflammation and septic shock. Septic shock occurs with an exacerbated inflammatory response that damages tissue mitochondria. Skeletal muscle appears as one of the main target organs in septic shock, showing an increased nitric oxide (NO) production, an early oxidative stress, and contractile failure. Mitochondria isolated from rat and human skeletal muscle in septic shock show a markedly increased NO generation and a decreased state 3 respiration, more marked with nicotinamide adenine dinucleotide (NAD)-linked substrates than with succinate, without uncoupling or impairment of phosphorylation. One of the current hypothesis for the molecular mechanisms of septic shock is that the enhanced NO production by mitochondrial nitric oxide synthase (mtNOS) leads to excessive peroxynitrite (ONOO(-)) production and protein nitration in the mitochondrial matrix, to mitochondrial dysfunction and to contractile failure. Surface chemiluminescence is a useful assay to assess inflammation and oxidative stress in in situ liver and skeletal muscle. Liver chemiluminescence in inflammatory processes and phagocyte chemiluminescence have been found spectrally different from spontaneous liver chemiluminescence with increased 440-600 nm emission, likely due to NO and ONOO(-) participation in the reactions leading to the formation of excited species.

Animals↗

PubMed2005

Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia.

Cachexia contributes to nearly a third of all cancer deaths, yet the mechanisms underlying skeletal muscle wasting in this syndrome remain poorly defined. We report that tumor-induced alterations in the muscular dystrophy-associated dystrophin glycoprotein complex (DGC) represent a key early event in cachexia. Muscles from tumor-bearing mice exhibited membrane abnormalities accompanied by reduced levels of dystrophin and increased glycosylation on DGC proteins. Wasting was accentuated in tumor mdx mice lacking a DGC but spared in dystrophin transgenic mice that blocked induction of muscle E3 ubiquitin ligases. Furthermore, DGC deregulation correlated positively with cachexia in patients with gastrointestinal cancers. Based on these results, we propose that, similar to muscular dystrophy, DGC dysfunction plays a critical role in cancer-induced wasting.

Adult↗