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PubMed1990

Ethanol-induced smooth and skeletal muscle myopathy: use of animal studies.

This article reviews the effects of ethanol on skeletal and smooth muscle. A brief summary of its clinical effects is provided, with a rationale for the use of suitable animal models to study ethanol-induced myotoxicity. Practical details are given for the animal feeding techniques to examine the chronic effects of ethanol toxicity. Information on acute ethanol dosage experiments are also provided. Our results have indicated that ethanol causes net loss of both skeletal and smooth muscle protein and an effect on protein synthesis and/or degradation was implicated. The theoretical and practical basis of measuring protein synthesis in intact laboratory animals is reviewed. However, there are no reliable methods for measuring rates of protein breakdown in vivo. The combined results of our studies indicated that disturbances in protein synthesis were causal mechanisms for ethanol-induced myo-dysfunction. Acute ethanol exposure was largely characterised by reductions in fractional rates of skeletal and smooth muscle contractile protein synthesis. The dominant characteristics of chronic treatments were loss of skeletal and smooth muscle proteins and RNA. Further laboratory animal studies will eventually elucidate the molecular mechanisms of these changes and provide valuable information on the regulation of protein mass.

Actomyosin↗

PubMed1995

Effects of exercise training in patients with congestive heart failure: a critical review.

Congestive heart failure is a potentially debilitating disorder that affects a significant number of patients. The age-adjusted death rate has doubled over the past decade. Patients live an average of 4 to 5 years, and nearly all suffer from fatigue and breathlessness, which limits exercise capacity and produces a poor quality of life. Patients have usually been advised to avoid exercise because of concerns that they would experience a further decline in cardiac function. However, it has been demonstrated that exercise capacity is not related to the degree of left ventricular systolic dysfunction. This has led to the suggestion that peripheral changes in skeletal muscle and blood supply may play a major role in determining the exercise capacity of patients with congestive heart failure. Studies have demonstrated abnormalities of skeletal muscle blood flow, metabolism and structure, all of which are consistent with the impaired performance observed in these patients. Although the effects of exercise training have been examined in only a relatively few number of patients, the results have been promising. Exercise training has been found to improve exercise capacity and reduce symptoms. However, to our knowledge no data exist as to the impact of exercise training on left ventricular function, hospital stay or mortality in this population. Even though the early results are promising, they require confirmation of feasibility, clinical benefit and safety in larger, long-term randomized trials. It should be determined whether training has a long-term beneficial impact on measures more closely related to daily activities and quality of life. Ultimately, it would be important to determine whether training has an impact on mortality and morbidity.

Clinical Trials as Topic↗

PubMed2003

The skeletal muscle channelopathies: distinct entities and overlapping syndromes.

PURPOSE OF REVIEW: This review outlines recent advances in clinical, genetic and molecular aspects of skeletal muscle channelopathies. RECENT FINDINGS: A new molecular genetic classification of skeletal muscle channelopathies has now emerged. This genetic classification complements previous clinical classifications. It is evident that there is considerable phenotypic diversity associated with dysfunction of a given muscle ion channel. Treatment response is likely to be related to genotype. DNA-based diagnosis is now achievable in most patients. SUMMARY: Ion channel dysfunction is now known to be the basis for familial variants of common neurological diseases such as migraine and epilepsy. Such discoveries were made possible through earlier work on the skeletal muscle channelopathies which remain the best understood example of all channelopathies. Classification of muscle channelopathies initially relied upon their specific clinical and neurophysiological features. This classification remains useful, but recent advances have led to a new system of classification based on the underlying molecular genetic defect. Recent advances have highlighted the broad phenotypic spectrum of muscle channelopathies and remarkable genetic heterogeneity is now recognized. DNA-based diagnosis is now available and should be achieved in all patients. Accurate genetic diagnosis is of major importance for accurate prognosis, for genetic counselling and has implications for therapeutics.

Animals↗

PubMed2005

Pathophysiology of peripheral muscle wasting in cardiac cachexia.

PURPOSE OF REVIEW: Many different mechanisms have been proposed to explain muscle wasting in patients with heart failure; however, the pathogenesis remains largely obscure. This manuscript looks at current developments concerning the pathophysiology of skeletal muscle wasting in cardiac cachexia. RECENT FINDINGS: Many studies have shown that malnutrition, malabsorption, metabolic dysfunction, anabolic/catabolic imbalance, inflammatory and neurohormonal activation, and cell death play an important role in the pathogenesis of wasting in cardiac cachexia. However, the aetiology of the muscle changes is not entirely clear. In biopsies of skeletal muscles from animals with cardiac cachexia increased rates of protein degradation have been observed, with increased activity of the ubiquitin-proteasome proteolytic pathway. Skeletal muscle apoptosis may also play a role in muscle atrophy and wasting and can be partly prevented by neurohormonal inhibition, but it has recently been reported that in cachectic patients with chronic heart failure apoptosis is not the main pathway of cell death and muscle loss. SUMMARY: Many hypotheses have been used to explain the pathogenesis of muscle wasting in cardiac cachexia. Cardiac cachexia is a multifactorial disorder, and the targeting of different pathways will be necessary for effective treatment. The immune and neurohormonal abnormalities present in chronic heart failure may play a significant role in the pathogenesis of the wasting process. It has been suggested that common pathogenetic mechanisms underlie the loss of muscle mass in different cachectic states. More studies are needed to show whether there is a common pathway in cardiac cachexia and the other cachectic states.

Apoptosis↗

PubMed1999

Exercise skeletal muscle blood flow is related to peripheral microvascular stiffness in idiopathic dilated cardiomyopathy.

Peripheral microvascular function plays an important role in congestive heart failure (CHF). Decreased exercise blood flow and microvascular dysfunction have been described in CHF and both factors are regarded as parameters that might influence exercise capacity in these patients. Whether these factors are related to or can be characterized in clinical severity of CHF has not been elucidated in this population. Skeletal muscle blood flow (SMBF) was measured continuously noninvasively, by means of the local isotope washout technique using (133)Xenon, in musculus tibialis anterior during graded maximal supine bicycle exercise. The distensibility in skeletal muscle was measured in a papaverine-relaxed vascular bed using (99m)Tc-pertechnetate. The investigation included 20 patients with moderate CHF (NYHA II), 11 patients with severe CHF (NYHA III, IV) due to idiopathic dilated cardiomyopathy (IDCM), and 31 age-matched healthy subjects. The maximal SMBF level was significantly lower in severe CHF (3.6 +/- 2.5 (ml x (100 g x min)(-1))) compared with moderate CHF (8.6 +/- 5.1 (ml x (100 g x min)(-1)); P < 0.005) and controls (11.0 +/- 4.1 (ml x (100 g x min)(-1)); P < 0.0001), but similar between moderate CHF and controls. Distensibility in skeletal muscle was decreased in severe CHF (12 +/- 8%) compared with controls (44 +/- 17%; P < 0.0001 vs severe CHF) and decreased with increasing severity of CHF (moderate CHF, 23 +/- 14%; P < 0.0005 vs controls). In CHF patients, a relationship was demonstrated between skeletal muscle distensibility and the maximal SMBF (P < 0.0001; r = 0.70). Moreover, maximal SMBF correlated directly to exercise time (P < 0.005; r = 0.54). Patients with CHF have reduced exercise SMBF, which may be a limiting factor for the reduced maximal exercise capacity. Moreover, microvascular distensibility in skeletal muscle is reduced and correlates to maximal exercise SMBF. Furthermore, maximal SMBF correlates to exercise time. This implies that increased skeletal muscle microvascular stiffness may contribute to the reduced blood flow during exercise and SMBF may partly limit exercise performance in CHF patients due to IDCM.

Adult↗

PubMed2005

Direct metabolic regulation in skeletal muscle and fat tissue by leptin: implications for glucose and fatty acids homeostasis.

In recent years, the adipose tissue has emerged as an important endocrine organ. It is now recognized that besides storing energy the adipocytes also secrete several bioactive peptides, collectively called adipocytokines. Among these adipocytokines, leptin, the product of the ob gene, has been extensively investigated over the last decade. Skeletal muscle and adipose tissue, two major tissues involved in the regulation of glucose and fatty acids metabolism, have been consistently demonstrated to be directly affected by leptin. By binding to its receptors located in skeletal muscle and fat cells, leptin promotes energy dissipation and prevents fatty acid accumulation and 'lipotoxicity' in these tissues. On the other hand, under conditions of peripheral leptin resistance, such as observed in obese humans, the activation of pathways involved in fatty acid oxidation may be impaired. This leads to intracellular accumulation of lipid intermediates and causes insulin resistance. This review examines the metabolic pathways that are directly activated by leptin and how it regulates glucose and fatty acids metabolism in skeletal muscle and fat tissue. Furthermore, the impact of peripheral leptin resistance in these tissues leading to dysfunctional metabolic adaptations is also discussed.

Adipose Tissue↗

PubMed1990

Pharmacological treatment of respiratory insufficiency.

The respiratory muscles, as any other skeletal muscle can fatigue. Respiratory muscle fatigue has been shown to play an important role in the pathogenesis of dyspnea and respiratory failure. Treatment of this respiratory muscle dysfunction appears therefore to be clinically important in patients with respiratory diseases. The respiratory muscles and particularly the diaphragm present some particularities among the skeletal muscles. The diaphragm excitation-contraction coupling processes and blood flow appear to be closer to the myocardium than to the peripheral skeletal muscles. Pharmacological agents that enhance respiratory muscle function by acting at these two levels may therefore be clinically useful. This review deals essentially with respiratory muscle dysfunction and its pharmacological approach.

Animals↗

PubMed2001

Impaired modulation of sympathetic vasoconstriction in contracting skeletal muscle of rats with chronic myocardial infarctions: role of oxidative stress.

Skeletal muscle perfusion during exercise is impaired in heart failure, but the underlying mechanisms are poorly understood. One possibility is that sympathetic vasoconstriction is enhanced in exercising muscle in heart failure as a result of impaired counterregulatory mechanisms that normally act to attenuate vasoconstrictor responses. In healthy animals, sympathetic vasoconstriction in contracting skeletal muscle is attenuated by endogenously produced nitric oxide (NO). Because the NO pathway may be dysfunctional in heart failure, we hypothesized that reduced NO in contracting muscle would result in enhanced sympathetic vasoconstriction. In sham rats and rats with chronic myocardial infarctions (MIs) produced by coronary artery ligation, we measured arterial pressure and femoral artery blood flow responses to sympathetic nerve stimulation (1, 2.5, and 5 Hz) in resting and contracting hindlimb. In resting hindlimb, sympathetic stimulation decreased femoral vascular conductance similarly in sham and MI rats. In contracting hindlimb, these vasoconstrictor responses were attenuated to a greater extent in sham than in MI rats. NO synthase inhibition enhanced sympathetic vasoconstriction in contracting hindlimb of sham, but not MI, rats. Conversely, infusion of L-arginine or a superoxide scavenger, tempol or tiron, attenuated sympathetic vasoconstriction in contracting hindlimb of MI rats. NO synthase expression was similar, but malondialdehyde (a marker of free radical damage) was greater in skeletal muscle from MI than from sham rats. These data suggest that impaired metabolic modulation of sympathetic vasoconstriction in contracting skeletal muscle of MI rats is a consequence of superoxide-mediated disruption of the NO pathway.

Animals↗

PubMed2005

Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells.

Skeletal myopathy is a common complication of endogenous and exogenous glucocorticoid excess, yet its pathogenetic mechanisms remain unclear. There is accumulating evidence that mitochondrial dysfunction and oxidative stress are involved in this process. To explore the glucocorticoid-induced transcriptional adaptations that may affect mitochondrial function in skeletal muscle, we studied gene expression profiles in dexamethasone-treated primary human skeletal myocytes using a cDNA microarray, which contains 501 mitochondria-related genes. We found that monoamine oxidase A (MAO-A) was the most significantly up-regulated gene. MAO-A is the primary enzyme metabolizing catecholamines and dietary amines, and its role in skeletal muscle remains largely unexplored. Dexamethasone induced dose- and time-dependent increases of MAO-A gene and protein expression, while its effects on MAO-B were minimal. Both the glucocorticoid receptor (GR) and the Sp1 transcription factor were required for dexamethasone-induced MAO-A mRNA expression, as blockade of the GR with RU 486 or ablation of Sp1 binding with mithramycin abrogated MAO-A mRNA induction. The observed dexamethasone effect was biologically functional, as this steroid significantly increased MAO-mediated hydrogen peroxide production. We suggest that MAO-A-mediated oxidative stress can lead to cell damage, representing a novel pathogenetic mechanism for glucocorticoid-induced myopathy and a potential target for therapeutic intervention.

Adolescent↗

PubMed2003

Targeting diastolic dysfunction by genetic engineering of calcium handling proteins.

Diastolic heart failure (HF) is associated with significant morbidity and mortality, and is a growing medical problem in this country. Diastolic dysfunction is defined as an abnormality in myocardial relaxation that impairs filling during diastole and contributes to the clinical syndrome of HF. Effective clinical strategies to treat diastolic dysfunction are limited. This article focuses on the potential application of parvalbumin--a fast skeletal muscle calcium buffer--for remediation of slow relaxation in the failing heart.

Diastole↗

PubMed1999

Absence of mitochondrial dysfunction in polymyalgia rheumatica. Evidence based on a simultaneous molecular and biochemical approach.

OBJECTIVE: To investigate the molecular and biochemical profile of skeletal muscle mitochondria of patients with isolated polymyalgia rheumatica (PMR). PATIENTS AND METHODS: We included patients with a recent diagnosis of PMR and as control healthy individuals submitted to orthopedic surgery. Skeletal muscle was obtained from quadriceps, thus was mitochondria immediately isolated. Long polymerase chain reaction and Southern blot transference were performed to detect deleted mtDNA molecules. Mitochondrial oxidative activity using different substrates and individual enzyme activity of respiratory chain complexes were assessed to search for any biochemical dysfunction. RESULTS: Fifty-one individuals (PMR=25, controls=26) were included. Mean age was 72 (11) years; 45% were females. We found no significant increase of deleted mtDNA molecules in PMR patients compared to controls. Both groups differed neither on oxygen consumption (p=NS for all substrates) nor enzymatic activity (p=NS for all complexes). CONCLUSIONS: Skeletal muscle mitochondria are molecularly and biochemically unaffected in PMR.

Adenosine Triphosphatases↗

PubMed2005

Mitochondrial dysfunction and type 2 diabetes.

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic beta cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.

Adenosine Triphosphate↗

PubMed1995

Changes in the peripheral circulation in heart failure.

Chronic heart failure is associated with neurohumoral activation and alterations of the peripheral circulation and skeletal muscle. Several mechanisms are involved in the impaired peripheral perfusion, including increased sympathetic tone and increased vascular stiffness. Recently, data have suggested an important role of the endothelium for perfusion of skeletal muscle in heart failure. Endothelium-dependent dilation of resistance vessels is blunted in patients with severe chronic heart failure. Conceivably, this abnormality may be involved in the impaired reactive hyperemia seen in patients with chronic heart failure. In conductance vessels, flow-dependent dilation is attenuated in patients with chronic heart failure as compared with normal subjects, indicating endothelial dysfunction of large conduit vessels. Dysfunctional endothelium may contribute to impaired tissue perfusion in heart failure. Beyond an impairment of perfusion, skeletal muscle itself is altered in chronic heart failure. The metabolic abnormalities of skeletal muscle in patients with heart failure do not result from inadequate O2 delivery, but from inadequate O2 utilization by mitochondria, consistent with previous findings that the oxidative capacity of mitochondria in skeletal muscle is reduced. It appears that the impaired muscular endurance in heart failure is related to an enhanced glycolytic metabolism secondary to the reduced oxidative capacity of skeletal muscle. The observed low muscular strength appears to be due to a smaller muscle cross-sectional area. Despite successful heart transplantation, only partial improvement of bioenergetic abnormalities was noted in patients 15 months after heart transplantation.

Blood Circulation↗

PubMed1998

Analysis of neuronal nitric oxide synthase isoform expression and identification of human nNOS-mu.

The neuronal form of nitric oxide synthase (nNOS) is responsible for the production of NO, which acts as a neurotransmitter for penile erection and urethra relaxation. An nNOS splice variant form, nNOS-mu, was first reported to be specifically expressed in skeletal muscle and heart in the rat, but later also identified in rat penile cavernosum. We report here an apparently universal expression of nNOS-mu mRNA in rat tissues, including brain, which was previously reported to be lacking nNOS-mu. Immunoblot analysis revealed that some commercially available nNOS antibodies had high levels of nonspecific activities, which could lead to the appearance of seemingly multiple forms of nNOS. Immunohistochemical analysis with these antibodies also produced nonspecific stainings. In humans, nNOS-mu; expression appeared to be confined to skeletal muscle and heart. Human penile tissues obtained from patients with erectile dysfunction did not express nNOS-mu. The human nNOS-mu-specific cDNA sequence was 89% homologous to its rat counterpart.

Alternative Splicing↗

PubMed1993

Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure.

Proposed reflex mechanisms for generalized neurohumoral activation in heart failure include decreased input from inhibitory baroreceptor afferent vessels and increased input from excitatory afferent vessels arising from arterial chemoreceptors, skeletal muscle metaboreceptors or the lungs. Not all subjects with left ventricular dysfunction have increased sympathetic nerve activity, but the magnitude of sympathoneural activation appears to independently predict survival. This association suggests both a causative mechanism linking sympathetic activation with adverse outcome and a therapeutic opportunity to improve the prognosis of such patients by inhibiting central sympathetic outflow. Generalized sympathetic activation is not unique to heart failure, and its functional consequences appear to be both organ- and condition-specific. Sympathetic activation is present in other disorders such as mild hypertension, cirrhosis and aging that do not share the dim prognosis of congestive heart failure. The adverse effects of adrenergic activation on the diseased myocardium may be a function of the magnitude and time course of increases in cardiac sympathetic nerve activity, the mechanical and electrophysiologic consequences of nonuniform abnormalities of sympathetic innervation in the failing heart and the absence of specific countervailing mechanisms present in other conditions also characterized by increased sympathetic traffic. The hypotheses that activation of adrenergic drive to the diseased myocardium is the causative mechanism linking sympathoexcitation to adverse outcome and that interventions that inhibit sympathetic outflow to the heart will improve the prognosis of patients with congestive heart failure have not been specifically tested. Greater understanding of the mechanisms responsible for the heterogeneity of sympathetic activation in response to ventricular dysfunction, for cardiac-specific and generalized activation of the sympathetic nervous system and for the stimulation or suppression of countervailing mechanisms capable of resisting its adverse effects is fundamental to the development of better therapies for congestive heart failure.

Heart↗

PubMed2001

Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease.

BACKGROUND: The LMNA gene, one of 6 autosomal disease genes implicated in familial dilated cardiomyopathy, encodes lamins A and C, alternatively spliced nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunnigan-type familial partial lipodystrophy, and dilated cardiomyopathy. METHODS AND RESULTS: Two 4-generation white families with autosomal dominant familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a missense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adult subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction disease but with earlier onset (third and fourth decades), ventricular dysrhythmias, left ventricular enlargement, and systolic dysfunction. Death was caused by heart failure and sudden cardiac death. Skeletal muscle disease was not observed in either family. CONCLUSIONS: Novel rod segment mutations in lamin A/C cause variable conduction system disease and dilated cardiomyopathy without skeletal myopathy.

Adult↗

PubMed2006

Muscle aging is associated with compromised Ca2+ spark signaling and segregated intracellular Ca2+ release.

Reduced homeostatic capacity for intracellular Ca2+ ([Ca2+]i) movement may underlie the progression of sarcopenia and contractile dysfunction during muscle aging. We report two alterations to Ca2+ homeostasis in skeletal muscle that are associated with aging. Ca2+ sparks, which are the elemental units of Ca2+ release from sarcoplasmic reticulum, are silent under resting conditions in young muscle, yet activate in a dynamic manner upon deformation of membrane structures. The dynamic nature of Ca2+ sparks appears to be lost in aged skeletal muscle. Using repetitive voltage stimulation on isolated muscle preparations, we identify a segregated [Ca2+]i reserve that uncouples from the normal excitation-contraction process in aged skeletal muscle. Similar phenotypes are observed in adolescent muscle null for a synaptophysin-family protein named mitsugumin-29 (MG29) that is involved in maintenance of muscle membrane ultrastructure and Ca2+ signaling. This finding, coupled with decreased expression of MG29 in aged skeletal muscle, suggests that MG29 expression is important in maintaining skeletal muscle Ca2+ homeostasis during aging.

Aging↗

PubMed1998

Evaluation of troponin-I as an indicator of cardiac dysfunction after thermal injury.

BACKGROUND: Biochemical serum markers commonly used to assess human cardiac injury (creatinine phosphokinase, creatine phosphokinase-MB) have been shown to have diminished specificity for detection of cardiac injury in the setting of burn-related soft-tissue and skeletal muscle injury. Laboratory studies have demonstrated that severe cutaneous thermal injury is associated with cardiac contractile dysfunction and a corresponding elevation in serum cardiac troponin-I (cTn-I) in several species. METHODS: Twenty-three patients admitted to a tertiary care burn referral center were evaluated. Patients were monitored with pulmonary artery catheters, and creatinine phosphokinase, creatine phosphokinase-MB, and cTn-I levels were determined for 24 hours. Using a database, 6,722 burn patients were reviewed to determine the incidence of preexisting cardiac disease and postburn cardiac complications. RESULTS: All patients had persistent sinus tachycardia (>115 beats per minute) without obvious electrical anomalies. All patients centrally monitored with a pulmonary artery catheter (n=20) maintained a cardiac index of greater than 3.0 L x min(-1) x m(-2) x cTn-I was present (>0.3 ng/mL) within 3.0 hours and elevated (>0.55 ng/mL) at 24 hours for all burns of more than 18% total body surface area. Historically, although only 5% of all admissions manifest acute postburn cardiac complications, 94% of these patients presented with preexisting heart disease. CONCLUSION: Severe thermal injury was associated with a mild elevation in serum troponin-I; however, this did not correlate with overt cardiac morbidity or mortality. Postburn elevation of cTn-I suggested that a subtle degree of cardiac injury was present after a severe thermal injury despite hyperdynamic cardiac function during resuscitation.

Biomarkers↗