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At least 289 records · Page 16Linked to original sources

PubMed2006

Stereological analysis of muscle morphology following exposure to repetitive stretch-shortening cycles in a rat model.

Repetitive motion is one risk factor associated with contraction-induced muscle injury, which leads to skeletal muscle degeneration, inflammation, and dysfunction. Since current methods are unable to quantify the acute degenerative and inflammatory responses of muscle tissue concurrently, the purpose of this study was to quantify the temporal myofiber response after exposure to injurious stretch-shortening cycles (SSCs) using a standardized stereological technique. Functional testing was performed on the ankle dorsiflexor muscles of Sprague-Dawley rats in vivo. Rats were anesthetized and exposed to 15 sets of 10 SSCs. Control rats were exposed to 15 sets of single isometric contractions of the same stimulation duration. Changes in muscle morphometry were assessed at 0.5, 24, 48, 72, and 240 h post-exposure to quantify the degree of myofiber degeneration and inflammation in the tibialis anterior muscle from each group. There was an increase in the volume density and average thickness of degenerating myofibers over time in the muscle collected from rats exposed to SSCs (p < 0.0001) that was significantly greater than in muscle exposed to isometric contractions at 24, 48, and 72 h post-exposure (p = 0.003). The volume density of degenerative myofibers was associated with functional deficits at 48 h. Stereological quantification of degenerative myofibers and interstitial space changes were associated with functional defects 48-72 h after SSC-induced injury, thus demonstrating stereology is an accurate measure of SSC-induced skeletal muscle injury.

Animals↗

PubMed2005

Tissue-specific mtDNA lesions and radical-associated mitochondrial dysfunction in human hearts exposed to doxorubicin.

Doxorubicin causes a chronic cardiomyopathy. Although the exact pathogenesis is unknown, recent animal data suggest that somatically acquired alterations of mitochondrial DNA (mtDNA) and concomitant mitochondrial dysfunction play an important role in its onset. In this study, skeletal and myocardial muscles were examined from human autopsies. Compared to controls (n = 8), doxorubicin-exposed hearts (n = 6) showed low absolute enzyme activity of mtDNA-encoded nicotinamide adenine dinucleotide hydrogen dehydrogenase (NADH DH, 79% residual activity, p = 0.03) and cytochrome c oxidase (COX, 59% residual activity, p < 0.001), but not of succinate dehydrogenase (SDH), which is encoded exclusively by nuclear DNA. NADH DH/SDH and COX/SDH ratios were 37% (p < 0.001) and 27% (p < 0.001) of controls. Expression of the mtDNA-encoded subunit II of COX was reduced (82%, p = 0.04), compared to its unchanged nucleus-encoded subunit IV. MtDNA-content was diminished (56%, p = 0.02), but the 'common' mtDNA-deletion was increased (9.2-fold, p = 0.004). Doxorubicin-exposed hearts harboured numerous additional mtDNA rearrangements lacking direct repeats. They contained elevated levels of malondialdehyde (MDA) (p = 0.006, compared to controls), which correlated inversely with the COX/SDH ratio (r = -0.45, p = 0.02) and the mtDNA-content (r = -0.75, p = 0.002), and correlated positively with the levels of the 'common' deletion (r = 0.80, p < 0.001). Doxorubicin-exposed hearts also contained the highest levels of superoxide (p < 0.001, compared to controls), which correlated negatively with the mtDNA-encoded respiratory chain activities, such as the COX/SDH ratio (r = -0.57, p = 0.02) and the NADH/SDH ratio (r = -0.52, p = 0.04), as well as with the mtDNA content (r = -0.69, p = 0.003), and correlated positively with the frequency of the 'common' deletion (r = 0.76, p < 0.001) and the MDA levels (r = 0.86, p < 0.001). Doxorubicin-exposed hearts contained electron-dense deposits within mitochondria. Hearts exposed to other anthracyclines (n = 6) or skeletal muscle (all groups) had no mitochondrial dysfunction. Doxorubicin, unlike other anthracyclines, augments lipid peroxidation, induces mtDNA mutations and decreases mtDNA content in human hearts. These lesions have an impact on mitochondrial function and could be of importance in the pathogenesis of clinical cardiomyopathy.

Adult↗

PubMed2004

Insights into the biology of diabetic vascular disease: what's new?

The major cause of morbidity and mortality in persons with diabetes is cardiovascular disease (CVD), the risk of which is increased three- to four-fold versus persons without diabetes. The biology of diabetes is characterized not only by hyperglycemia but also by hypertension, dyslipidemia, microalbuminuria, inflammation, and abnormal thrombolysis. Hypertension is a common feature of diabetes and is the primary contributor to CVD. Recent investigations have revealed a relationship between vascular derangements, insulin resistance, and visceral obesity and have implicated the renin-angiotensin-aldosterone system (RAAS) as a key mediator of cardiovascular dysfunction in diabetes. Angiotensin II has been shown to have direct effects on endothelial dysfunction, oxidative stress, inflammation, skeletal muscle, and adipocyte function. These pathophysiologic considerations have formed the basis for CVD prevention strategies in diabetes. Clinical trials have demonstrated a reduction in cardiovascular events with aspirin, lipid-lowering agents, and antihypertensive agents. Blood pressure (BP) control (<130/80 mm Hg) is a crucial component of risk reduction, and several studies have demonstrated the need for multiple agents to reach therapeutic goals. Clinical trials also demonstrated the benefit of RAAS blocking agents in reducing BP and cardiovascular and renal risk, and suggest clinical benefits beyond BP reduction.

Diabetic Angiopathies↗

PubMed2006

Hypomorphic mutation of PGC-1beta causes mitochondrial dysfunction and liver insulin resistance.

PGC-1beta is a transcriptional coactivator that potently stimulates mitochondrial biogenesis and respiration of cells. Here, we have generated mice lacking exons 3 to 4 of the Pgc-1beta gene (Pgc-1beta(E3,4-/E3,4-) mice). These mice express a mutant protein that has reduced coactivation activity on a subset of transcription factors, including ERRalpha, a major target of PGC-1beta in the induction of mitochondrial gene expression. The mutant mice have reduced expression of OXPHOS genes and mitochondrial dysfunction in liver and skeletal muscle as well as elevated liver triglycerides. Euglycemic-hyperinsulinemic clamp and insulin signaling studies show that PGC-1beta mutant mice have normal skeletal muscle response to insulin but have hepatic insulin resistance. These results demonstrate that PGC-1beta is required for normal expression of OXPHOS genes and mitochondrial function in liver and skeletal muscle. Importantly, these abnormalities do not cause insulin resistance in skeletal muscle but cause substantially reduced insulin action in the liver.

Animals↗

PubMedDate not supplied

Carnitine-acylcarnitine translocase deficiency, clinical, biochemical and genetic aspects.

The carnitine-acylcarnitine translocase (CACT) is one of the components of the carnitine cycle. The carnitine cycle is necessary to shuttle long-chain fatty acids from the cytosol into the intramitochondrial space where mitochondrial beta-oxidation of fatty acids takes place. The oxidation of fatty acids yields acetyl-coenzyme A (CoA) units, which may either be degraded to CO(2) and H(2)O in the citric acid cycle to produce ATP or converted into ketone bodies which occurs in liver and kidneys. Metabolic consequences of a defective CACT are hypoketotic hypoglycaemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and an abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical signs and symptoms in CACT deficient patients, are a combination of energy depletion and endogenous toxicity. The predominantly affected organs are brain, heart and skeletal muscle, and liver, leading to neurological abnormalities, cardiomyopathy and arrythmias, skeletal muscle damage and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have also been reported. The therapeutic approach is the same as in other long-chain fatty acid disorders and includes intravenous glucose (+/- insulin) administration to maximally inhibit lipolysis and subsequent fatty acid oxidation during the acute deterioration, along with other measures such as ammonia detoxification, depending on the clinical features. Long-term strategy consists of avoidance of fasting with frequent meals and a special diet with restriction of long-chain fatty acids. Due to the extremely low free carnitine concentrations, carnitine supplementation is often needed. Acylcarnitine profiling in plasma is the assay of choice for the diagnosis at a metabolite level. However, since the acylcarnitine profile observed in CACT-deficient patients is identical to that in CPT2-deficient patients, definitive identification of CACT-deficiency in a certain patient requires determination of the activity of CACT. Subsequently, mutational analysis of the CACT gene can be performed. So far, 9 different mutations have been identified in the CACT gene.

Animals↗

PubMed2000

[Pathophysiological basis of heart failure].

The progression of heart failure is related to local and systemic neuroendocrine activation. On the level of the myocardium, neuroendocrine activation (angiotensin II, endothelin, aldosterone, norepinephrine) as well as mediators of inflammation and free oxygen radicals contribute to hypertrophy, dilation and remodeling of the ventricles. In addition, vascular endothelial dysfunction and alterations of skeletal muscle contribute to clinical symptoms of heart failure patients. Changes in ventricular geometry during the progression of cardiac disease are associated with specific subcellular alterations on the level of the myocytes. Especially, disturbed intracellular Ca2+ handling resulting in altered excitation contraction coupling may lead to impaired systolic and diastolic function. Disturbed Ca2+ homeostasis has been associated with reduced re-uptake capacity of the sarcoplasmic reticulum for Ca2+ and an enhanced activity of the sarcolemmal Na+/Ca(2+)-exchanger. In consequence, alterations in force-frequency behavior were attributed to a decline in intracellular Ca2+ transients at higher stimulation rates. The reduced expression and desensitization of myocardial beta-adrenoceptors and alterations on the level of the G-proteins result in a reduced basal and catecholamine-stimulated activity of adenylate cyclase and a reduction in intracellular cAMP content. In consequence, reduced phosphorylation of intracellular functional proteins in the failing human heart contributes to altered Ca2+ handling. The Frank-Starling mechanism seems to be unaltered in isolated human myocardium from failing hearts. Endothelin and angiotensin may contribute to the regulation of myocardial contractility in the human heart, but their functional relevance in the regulation of myocardial contractility under clinical conditions remains to be evaluated.

Calcium Channels↗

PubMed1988

Deviations in hepatic amino acid profiles of mouse following repeated hexachlorophene administration.

Effects of repeated administration of hexachlorophene (HCP) on the food consumption, body and liver weights, liver somatic indices and hepatic levels of the free amino acids and amino acid-enzyme activities have been studied. A dose-dependent reduction in body weights and food consumption and increased liver somatic indices suggested a progressive and on toward response to HCP. The concentrations of hepatic free amino acids: phenylalanine, tyrosine, leucine, isoleucine, valine, threonine, asparagine, glutamic acid and glutamine were significantly (p less than 0.001) increased while serine, glycine, taurine and alanine levels were unaffected. The aspartic acid levels showed a conspicuous decrement. The specific activity patterns of the amino acid-enzymes denoted reduced oxidation of amino acids in liver. The abnormal rise in branched chain and aromatic amino acids could be due to the reduced utilization because of the depletion of skeletal muscle mass and hepatic dysfunction in HCP intoxication. A pronounced reduction in aspartic acid levels may deserve consideration in the manifestation of hyperammonemia and neurologic symptoms in HCP intoxication.

Alanine Transaminase↗

PubMed1997

Skeletal muscle extra-aortic counterpulsation in dogs with dilated cardiomyopathy.

Skeletal muscle extra-aortic counterpulsation was performed in seven dogs with dilated cardiomyopathy. A left latissimus dorsi dynamic descending thoracic aortomyoplasty was used as the autologous counterpulsator. Pulse train stimulation in diastole was used to initiate contraction and fibre type transformation. Two of the dogs died within 48 hours of surgery. The device was successfully activated in the five remaining dogs, but in one individual it failed within 48 hours of activation. Serial echocardiographic examinations of dogs in which the device functioned successfully (n = 4) showed trends towards the decrease in the left ventricular systolic internal dimension, left ventricular diastolic internal dimension, E-point to septal separation and left atrial diameter in systole seven to 14 days following the procedure, although these changes failed to persist in the long-term. The results suggest that skeletal muscle for cardiac assistances such as extra-aortic muscle counterpulsation, might be a therapeutic option for dogs with cardiac failure due to dilated cardiomyopathy.

Animals↗

PubMed2006

Identification of a beta-dystroglycan immunoreactive subcompartment in photoreceptor terminals.

PURPOSE: Mutations in the dystrophin-associated glycoprotein complex (DGC) cause various forms of muscular dystrophy. These diseases are characterized by progressive loss of skeletal muscle tissue and by dysfunctions in the central nervous system (CNS). The CNS deficits include an altered electroretinogram, caused by an impaired synaptic transmission between photoreceptors and their postsynaptic target cells in the outer plexiform layer (OPL). The DGC is concentrated in the OPL but its exact distribution is controversial. Therefore, the precise distribution of beta-dystroglycan, the central component of the DGC, within the OPL of the mature chick retina, was determined. METHODS: Double immunolabeling with antibodies against beta-dystroglycan and against Bassoon, a component of the presynaptic cytomatrix, concentrated at the insertion point of the synaptic ribbon into the active zone of the photoreceptor synapses, showed a nonoverlapping distribution of both proteins within individual rod and cone photoreceptor terminals. The three-dimensional distribution of the DGC within the photoreceptor terminals was determined by reconstruction of the beta-dystroglycan immunoreactivity from serial electron microscopic sections. RESULTS: We found that beta-dystroglycan was not directly associated with the ribbon synapse but instead concentrated perisynaptically in processes extending from the photoreceptors into the OPL. The processes displayed dystroglycan immunoreactivity primarily along their lateral sides and at their tips. Processes from bipolar or horizontal cells were not labeled. CONCLUSIONS: The perisynaptic concentration of beta-dystroglycan in photoreceptor terminals suggests a novel domain within photoreceptor terminals with functions in synaptic transmission.

Animals↗

PubMed2004

Cardiopulmonary exercise testing and prognosis in chronic heart failure: a prognosticating algorithm for the individual patient.

The identification of individuals who are at high risk of chronic heart failure (HF) is a medical art of growing concern. Cardiopulmonary exercise stress testing (CPX) has become an important clinical tool to predict outcome. The value of peak oxygen consumption rests in the fact that it integrates elements of cardiac adaptations, and skeletal muscle, pulmonary, and endothelial dysfunctions more than other traditional prognostic indicators of chronic HF. Recently, exercise-related ventilatory abnormalities have gained attention, stimulating scientific debate and an innovative perspective. This review, through a critical examination of previous experiences, will focus on the prognostic application of CPX, defining a proficient outline of treatment for the individual patient.

Algorithms↗

PubMed2006

Chronic obstructive pulmonary disease: diagnostic considerations.

Chronic obstructive pulmonary disease is characterized by the gradual progression of irreversible airflow obstruction and increased inflammation in the airways and lung parenchyma that is generally distinguishable from the inflammation caused by asthma. Most chronic obstructive pulmonary disease is associated with smoking, but occupational exposure to irritants and air pollution also are important risk factors. Patients with chronic obstructive pulmonary disease typically present with coughing, sputum production, and dyspnea on exertion. However, none of these findings alone is diagnostic. The Global Initiative for Chronic Obstructive Lung Disease diagnostic criterion for chronic obstructive pulmonary disease is a forced expiratory volume in one second/forced vital capacity ratio of less than 70 percent of the predicted value. Severity is further stratified based on forced expiratory volume in one second and symptoms. Chest radiography may rule out alternative diagnoses and comorbid conditions. Selected patients should be tested for alpha1-antitrypsin deficiency. Arterial blood gas testing is recommended for patients presenting with signs of severe disease, right-sided heart failure, or significant hypoxemia. Chronic obstructive pulmonary disease also is a systemic disorder with weight loss and dysfunction of respiratory and skeletal muscles.

Diagnosis, Differential↗

PubMed1998

[New aspects of the pathophysiology of heart failure].

The progression of heart failure is related to activation of neuroendocrine hormone systems. On the level of the myocardium, they contribute to hypertrophy, dilation and remodeling of the ventricles. In addition, vascular alterations with endothelial dysfunction and alterations of skeletal muscle contribute to clinical symptoms of heart failure patients. Changes in ventricular geometry during the progression of cardiac diseases are associated with specific subcellular alterations on the level of the myocytes. Especially, disturbed intracellular Ca2+ handling resulting in altered excitation contraction coupling may lead to impaired systolic and diastolic function. Disturbed Ca2+ homeostasis has been associated with reduced re-uptake capacity of the sarcoplasmic reticulum for Ca2+ and an enhanced activity of the sarcolemmal Na+/Ca2+ exchange. In consequence, alterations in force-frequency behavior were attributed to a decline in intracellular Ca2+ transients at higher stimulation rates. The reduced expression of myocardial beta-adrenoceptors and alterations on the level of the G-proteins result in a reduced activity of adenylate cyclase and reduction in intracellular cAMP content of the myocytes. In consequence, reduced phosphorylation of intracellular functional proteins in the failing human heart contributes to altered Ca2+ handling. The Frank-Starling-mechanism seems to be unaltered in failing isolated human myocardium. Endothelin and angiotensin may contribute to the regulation of myocardial contractility in the human heart, but their functional relevance in the regulation of myocardial contractility under clinical conditions remains to be evaluated.

Animals↗

PubMed2006

Increased lipid availability impairs insulin-stimulated ATP synthesis in human skeletal muscle.

Insulin resistance correlates with intramyocellular lipid content (IMCL) and plasma free fatty acids (FFAs) and was recently linked to mitochondrial dysfunction. We examined the underlying relationships by measuring skeletal muscle ATP synthase flux, glucose transport/phosphorylation, and IMCL in response to different plasma insulin and plasma FFA concentrations. Healthy men were studied twice during hyperinsulinemic-euglycemic clamps with (LIP) or without (CON) lipid infusion (plasma FFA: CON approximately 36 vs. LIP approximately 1,034 micromol/l, P < 0.001). ATP synthase flux, glucose-6-phosphate (G6P), and IMCL were determined before and during the clamp in calf muscle using (31)P and (1)H magnetic resonance spectroscopy. Plasma lipid elevation resulted in approximately 46% reduced whole-body glucose metabolism (180-360 min; P < 0.0001 vs. CON) and a 70% lower rise of G6P (P < 0.05 vs. CON) without significant changes in IMCL (LIP 117 +/- 12% vs. CON 93 +/- 3% of basal, P = 0.073). During the clamp, ATP synthase flux increased by approximately 60% under control conditions (P = 0.02 vs. baseline) and was 24% lower during lipid infusion (LIP 11.0 +/- 0.9 vs. CON 14.6 +/- 1.2 micromol . g muscle(-1) . min(-1), P < 0.05). Physiologically increased plasma FFA concentrations reduce insulin-stimulated muscle ATP synthase flux in parallel with induction of insulin resistance.

Adenosine Triphosphate↗

PubMed2002

[Adaptation in properties of skeletal muscle to coronary artery occlusion/reperfusion in rats].

The present study was designed to determine if changes in function and metabolism of heart muscle induce alterations in characteristics of skeletal muscle. We investigated the histochemical and biochemical properties of soleus (SOL) and extensor digitorum longus (EDL) muscles in Wistar rats at the chronic phase after coronary artery occlusion/reperfusion. The size of myocardial infarct region was evaluated using a high resolution pinhole single photo emission computed tomography (SPECT) system. 4 wk after left coronary artery occlusion/reperfusion, the SOL and EDL of hindlimb were dissected out and immersed in isopentane cooled with liquid nitrogen for subsequent histochemical and biochemical analysis. From SPECT imaging, the blood circulation was recovered, but the recovery of fatty acid metabolism was not observed in infarct region of heart. Citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activities in infarct region of heart were lower in the myocardial infarction (MI, n = 6) group compared with that of age-matched sham-operated (Sham, n = 6) group. In addition, heart muscle hypertrophy caused by the dysfunction in MI group was observed. In skeletal muscle, the atrophy and transition of fiber type distribution in MI group, reported in previous studies of heart failure, were not observed. However, the succinate dehydrogenase (SDH) activity in the slow twitch oxidative (SO) from SOL of MI group decreased by 9.8% and in the fast twitch oxidative glycolytic fibers (FOG), 8.0% as compared with sham group. Capillary density of the SO fibers from SOL of MI group also reduced by 18.5% and in the FOG fibers, 18.2% as compared with Sham group. Decreased capillary density in this study related significantly to decreased SDH activity of single muscle fibers in chronic phase of perfusion after surgical infarction. Our results make it clear that there is a difference in the reaction of skeletal muscle to coronary artery occlusion/reperfusion compared with chronic heart failure. However, our data would support the notion that there is a linkage between the function of heart and physiological properties of skeletal muscle.

3-Hydroxyacyl CoA Dehydrogenases↗

PubMed2002

[Kennedy syndrome--bulbo-spinal muscular atrophy].

Kennedy syndrome is a late-onset, bulbar-spinal type of muscular atrophy, with X-linked recessive inheritance. The characteristic features of the disease become prominent in the 4-5th decades: proximal muscle wasting and weakness, bulbar signs, fasciculations in skeletal muscles, subtle signs of endocrine dysfunction, such as gynaecomastia or testicular atrophy. The electrophysiological examinations are the keypoint to the diagnosis. Electroneurography shows normal conduction velocity in peripheral nerves, but the sensory nerves usually show axonal degeneration, which causes only very mild or subclinical neurological deficits. Electromyography shows chronic anterior horn cell degeneration in skeletal muscles. Molecular genetic diagnosis was introduced in 1991, when on abnormal expansion of CAG repeat was found in the first exon of the androgen receptor gene on chromosome X with a frequency of 100% in the affected population. Since the progression is very slow and these patients can expect a normal life span, it is essential to distinguish this syndrome from other, often more severe diseases, such as ALS. There is no proven therapy for Kennedy's disease yet. This is the first case of Kennedy's disease published in Hungary.

Adult↗

PubMed2000

Modulation of vascular endothelial gene expression by physical training in patients with chronic heart failure.

BACKGROUND: Abnormalities of the skeletal muscle vasculature, such as endothelial dysfunction and reduced microvascular density, can be reversed by physical training in patients with chronic heart failure. The molecular mechanisms that mediate the beneficial effects of physical training on the vascular endothelium are unknown. METHODS: Endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) gene expression in the skeletal muscle, peak oxygen consumption (VO2) and calf peak reactive hyperemia were measured before and after 12 weeks of supervised physical training in 10 patients with chronic heart failure. Five patients with heart failure of similar severity who did not participate in the training program served as controls. RESULTS: The effects of physical training on eNOS and VEGF gene expression were heterogeneous. eNOS gene expression increased 3-4 fold in 4 patients while it remained constant in 6 patients. VEGF gene expression increased significantly in all patients who were not treated with beta-adrenergic blockade and remained constant in all patients who were treated with beta-adrenergic blockade. In contrast, physical training increased peak VO2 and calf peak reactive hyperemia in all patients. Mean peak VO2 increased from 13.13 +/- 2.21 to 16.19 +/- 2.69 ml/kg/min (p < 0.001) and calf peak reactive hyperemia increased from 19.7 +/- 2.3 to 29.6 +/- 4.0 ml*min(-1)*100 ml(-1) (p < 0.001). CONCLUSIONS: A supervised program of physical training that consistently enhanced peak VO2 and vascular reactivity in patients with chronic heart failure increased or left eNOS and VEGF gene expression unchanged in skeletal muscle. Changes in vascular endothelial gene expression may contribute to the benefits of training on vascular endothelial function but are not solely responsible for these benefits.

Aged↗

PubMed1999

A missense mutation in canine C1C-1 causes recessive myotonia congenita in the dog.

Myotonia congenita is an inherited disorder of sarcolemmal excitation leading to delayed relaxation of skeletal muscle following contractions. Mutations in a skeletal muscle voltage-dependent chloride channel, CIC-1, have been identified as the molecular genetic basis for the syndrome in humans, and in two well characterized animal models of the disease: the myotonic goat, and the arrested development of righting (adr) mouse. We now report the molecular genetic and electrophysiological characterization of a canine CIC-1 mutation that causes autosomal recessive myotonia congenita in miniature Schnauzers. The mutation results in replacement of a threonine residue in the D5 transmembrane segment with methionine. Functional characterization of the mutation introduced into a recombinant CIC-1 and heterologously expressed in a cultured mammalian cell line demonstrates a profound effect on the voltage-dependence of activation such that mutant channels have a greatly reduced open probability at voltages near the resting membrane potential of skeletal muscle. The degree of this dysfunction is greatly diminished when heterodimeric channels containing a wild-type and mutant subunit are expressed together as a covalent concatemer strongly supporting the observed recessive inheritance in affected dog pedigrees. Genetic and electrophysiological characterization of the myotonic dog provides a new and potentially valuable animal model of an inherited skeletal muscle disease that has advantages over existing models of myotonia congenita.

Amino Acid Sequence↗

PubMed2002

Mouse models of insulin resistance.

The hallmarks of type 2 diabetes are impaired insulin action in peripheral tissues and decreased pancreatic beta-cell function. Classically, the two defects have been viewed as separate entities, with insulin resistance arising primarily from impaired insulin-dependent glucose uptake in skeletal muscle, and beta-cell dysfunction arising from impaired coupling of glucose sensing to insulin secretion. Targeted mutagenesis and transgenesis involving components of the insulin action pathway have changed our understanding of these phenomena. It appears that the role of insulin signaling in the pathogenesis of type 2 diabetes has been overestimated in classic insulin target tissues, such as skeletal muscle, whereas it has been overlooked in liver, pancreatic beta-cells, and brain, which had been thought not to be primary insulin targets. We review recent progress and try to reconcile areas of apparent controversy surrounding insulin signaling in skeletal muscle and pancreatic beta-cells.

Animals↗