Showing papers in "Essays in Biochemistry in 2006"

The anti-inflammatory effect of exercise: its role in diabetes and cardiovascular disease control.

Abstract: Chronic low-grade systemic inflammation is a feature of chronic diseases such as cardiovascular disease and type 2 diabetes. Regular exercise offers protection against all-cause mortality, primarily by protection against atherosclerosis and insulin resistance and there is evidence that physical training is effective as a treatment in patients with chronic heart diseases and type 2 diabetes. Regular exercise induces anti-inflammatory actions. During exercise, IL-6 (interleukin-6) is produced by muscle fibres. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra (interleukin-1 receptor antagonist) and IL-10 (interleukin-10) and inhibits the production of the pro-inflammatory cytokine TNF-alpha (tumour necrosis factor-alpha). In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. It is suggested that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine, that is produced and released by contracting skeletal muscle fibres, exerting its effects in other organs of the body. Myokines may be involved in mediating the beneficial health effects against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.

Fatty acid metabolism in adipose tissue, muscle and liver in health and disease.

Abstract: Fat is the largest energy reserve in mammals Most tissues are involved in fatty acid metabolism, but three are quantitatively more important than others: adipose tissue, skeletal muscle and liver Each of these tissues has a store of triacylglycerol that can be hydrolysed (mobilized) in a regulated way to release fatty acids In the case of adipose tissue, these fatty acids may be released into the circulation for delivery to other tissues, whereas in muscle they are a substrate for oxidation and in liver they are a substrate for re-esterification within the endoplasmic reticulum to make triacylglycerol that will be secreted as very-low-density lipoprotein These pathways are regulated, most clearly in the case of adipose tissue Adipose tissue fat storage is stimulated, and fat mobilization suppressed, by insulin, leading to a drive to store energy in the fed state Muscle fatty acid metabolism is more sensitive to physical activity, during which fatty acid utilization from extracellular and intracellular sources may increase enormously The uptake of fat by the liver seems to depend mainly upon delivery in the plasma, but the secretion of very-low-density lipoprotein triacylglycerol is suppressed by insulin There is clearly cooperation amongst the tissues, so that, for instance, adipose tissue fat mobilization increases to meet the demands of skeletal muscle during exercise When triacylglycerol accumulates excessively in skeletal muscle and liver, sometimes called ectopic fat deposition, then the condition of insulin resistance arises This may reflect a lack of exercise and an excess of fat intake

Resistance exercise, muscle loading/unloading and the control of muscle mass.

Abstract: Muscle mass is determined by the difference between the rate of protein synthesis and degradation. If synthesis is greater than degradation, muscle mass will increase (hypertrophy) and when the reverse is true muscle mass will decrease (atrophy). Following resistance exercise/increased loading there is a transient increase in protein synthesis within muscle. This change in protein synthesis correlates with an increase in the activity of protein kinase B/Akt and mTOR (mammalian target of rapamycin). mTOR increases protein synthesis by increasing translation initiation and by inducing ribosomal biogenesis. By contrast, unloading or inactivity results in a decrease in protein synthesis and a signifi cant increase in muscle protein breakdown. The decrease in synthesis is due in part to the inactivation of mTOR and therefore a decrease in translation initiation, but also to a decrease in the rate of translation elongation. The increase in degradation is the result of a co-ordinated response of the calpains, lysosomal proteases and the ATP-dependent ubiquitin-proteosome. Caspase 3 and the calpains act upstream of the ubiquitin–proteosome system to assist in the complete breakdown of the myofi brillar proteins. Two muscle specifi c E3 ubiquitin ligases, MuRF1 and MAFbx/atrogen-1, have been identifi ed as

Control of gene expression and mitochondrial biogenesis in the muscular adaptation to endurance exercise.

Abstract: Every time a bout of exercise is performed, a change in gene expression occurs within the contracting muscle. Over the course of many repeated bouts of exercise (i.e. training), the cumulative effects of these alterations lead to a change in muscle phenotype. One of the most prominent of these adaptations is an increase in mitochondrial content, which confers a greater resistance to muscle fatigue. This essay reviews current knowledge on the regulation of exercise-induced mitochondrial biogenesis at the molecular level. The major steps involved include, (i) transcriptional regulation of nuclear-encoded genes encoding mitochondrial proteins by the coactivator peroxisome-proliferator-activated receptor g coactivator-1, (ii) control of mitochondrial DNA gene expression by the transcription factor Tfam, (iii) mitochondrial fission and fusion mechanisms, and (iv) import of nuclear-derived gene products into the mitochondrion via the protein import machinery. It is now known that exercise can modify the rates of several of these steps, leading to mitochondrial biogenesis. An understanding of how exercise can produce this effect could help us decide whether exercise is beneficial for patients suffering from mitochondrial disorders, as well as a variety of metabolic diseases.

Resistance training, insulin sensitivity and muscle function in the elderly.

Abstract: Ageing is associated with a loss in both muscle mass and in the metabolic quality of skeletal muscle. This leads to sarcopenia and reduced daily function, as well as to an increased risk for development of insulin resistance and type 2 diabetes. A major part, but not all, of these changes are associated with an age-related decrease in the physical activity level and can be counteracted by increased physical activity of a resistive nature. Strength training has been shown to improve insulin-stimulated glucose uptake in both healthy elderly individuals and patients with manifest diabetes, and likewise to improve muscle strength in both elderly healthy individuals and in elderly individuals with chronic disease. The increased strength is coupled to improved function and a decreased risk for fall injuries and fractures. Elderly individuals have preserved the capacity to improve muscle strength and mass with training, but seem to display a reduced sensitivity towards stimulating protein synthesis from nutritional intake, rather than by any reduced response in protein turnover to exercise.

Effects of acute exercise and training on insulin action and sensitivity: focus on molecular mechanisms in muscle.

Abstract: A single bout of exercise increases insulin sensitivity for several hours and the effect is mainly restricted to the muscles recruited during exercise. When exercise is repeated over time, adaptations to physical training occur that include more long-lasting increases in insulin sensitivity. The present review explores the molecular mechanisms involved in both the acute and chronic effects of exercise on insulin sensitivity in skeletal muscle.

Lipid metabolism, exercise and insulin action

Abstract: Skeletal muscle constitutes 40% of body mass and takes up 80% of a glucose load. Therefore, impaired glucose removal from the circulation, such as that which occurs in obesity and type 2 diabetes, is attributable in large part to the insulin resistance in muscle. Recent research has shown that fatty acids, derived from adipose tissue, can interfere with insulin signalling in muscle. Hence, insulin-stimulated GLUT4 translocation to the cell surface is impaired, and therefore, the rate of glucose removal from the circulation into muscle is delayed. The mechanisms provoking lipid-mediated insulin resistance are not completely understood. In sedentary individuals, excess intramyocellular accumulation of triacylglycerols is only modestly associated with insulin resistance. In contrast, endurance athletes, despite accumulating large amounts of intramyocellular triacylglycerols, are highly insulin sensitive. Thus it appears that lipid metabolites, other than triacylglycerols, interfere with insulin signalling. These metabolites, however, are not expected to accumulate in athletic muscles, as endurance training increases the capacity for fatty acid oxidation by muscle. These observations, and others in severely obese individuals and type 2 diabetes patients, suggest that impaired rates of fatty acid oxidation are associated with insulin resistance. In addition, in obesity and type 2 diabetes, the rates of fatty acid transport into muscle are also increased. Thus, excess intracellular lipid metabolite accumulation, which interferes with insulin signalling, can occur as a result of impaired rates of fatty acid oxidation and/or increased rates of fatty acid transport into muscle. Accumulation of excess intramyocellular lipid can be avoided by exercise, which improves the capacity for fatty acid oxidation.

Signalling mechanisms in skeletal muscle: role in substrate selection and muscle adaptation

Abstract: Exercise produces a multitude of time- and intensity-dependent physiological, biochemical and molecular changes within skeletal muscle. With the onset of contractile activity, cytosolic and mitochondrial [Ca(2+)] levels are rapidly increased and, depending on the relative intensity of the exercise, metabolite concentrations change (i.e. increases in [ADP] and [AMP], decreases in muscle creatine phosphate and glycogen). These contraction-induced metabolic disturbances activate several key kinases and phosphatases involved in signal transduction. Important among these are the calcium dependent signalling pathways that respond to elevated Ca(2+) concentrations (including Ca(2+)/calmodulin-dependent kinase, Ca(2+)-dependent protein kinase C and the Ca(2+)/calmodulin-dependent phosphatase calcineurin), the 5'-adenosine monophosphate-activated protein kinase, several of the mitogen-activated protein kinases and protein kinase B/Akt. The role of these signal transducers in the regulation of carbohydrate and fat metabolism in response to increased contractile activity has been the focus of intense research efforts during the past decade.

Vascular nitric oxide: effects of physical activity, importance for health.

Abstract: NO (nitric oxide), formed in the vascular endothelium and derived from a biochemical reaction catalysed by eNOS (endothelial NO synthase), appears to play a role in exercise-induced dilation of blood vessels supplying cardiac and skeletal muscle. Endothelium-dependent, NO-mediated vasodilation is augmented by exercise training. Increases in eNOS gene transcription, eNOS mRNA stability and eNOS protein translation appear to contribute to increased NO formation and, consequently, enhanced NO-mediated vasodilation after training. Enhanced endothelial NO formation may also have a role(s) in the prevention and management of atherosclerosis because several steps in the atherosclerotic disease process are inhibited by NO. A growing body of work suggests that exercise training, perhaps via increased capacity for NO formation, retards atherosclerosis. This has significant implications for human health, given that atherosclerosis is the leading killer in Western society.

Vascular function in the metabolic syndrome and the effects on skeletal muscle perfusion: lessons from the obese Zucker rat.

Abstract: The increased prevalence of obesity in Western society has been well established for many years, and with this trend, the prevalence of other associated pathologies including insulin resistance, dyslipidaemia, hypertension and the genesis of a proinflammatory and prothrombotic environment within individuals is also rapidly increasing, resulting in a condition known as the~metabolic syndrome. From a physiological perspective, one of the most severe consequences of the metabolic syndrome is a progressive inability of the cardiovascular system to adequately perfuse tissues and organs during either elevated metabolic demand and, if sufficiently severe, under basal levels of demand. For the study of the metabolic syndrome, the OZR (obese Zucker rat) represents an important tool in this effort, as the metabolic syndrome in these animals results from a chronic hyperphagia, and thus can be an excellent representation of the human condition. As in afflicted humans, OZR experience an attenuated functional and reactive hyperaemia, and can ultimately experience an ischaemic condition in their skeletal muscles at rest. The source of this progressive ischaemia appears to lie at multiple sites, as endothelium-dependent vasodilator responses are strongly impaired in OZR, and specific constrictor processes (e.g. adrenergic tone) may be enhanced. Whilst these active processes may contribute to a reduction in blood flow under resting conditions or with mild elevations in metabolic demand, an evolving structural alteration to individual microvessels (reduced distensibility) and microvascular networks (reduced microvessel density) also develop and may act to constrain perfusion at higher levels of metabolic demand. Given that constrained muscle perfusion in the metabolic syndrome appears to reflect a highly integrated, multi-faceted effect in OZR, and probably in humans as well, therapeutic interventions must be designed to address each of these contributing elements.

Microvascular dysfunction: causative role in the association between hypertension, insulin resistance and the metabolic syndrome?

Abstract: The metabolic syndrome defines a clustering of metabolic risk factors that confers an increased risk for type 2 diabetes and cardiovascular disease. The metabolic syndrome seems to have multiple etiological factors and microvascular dysfunction may be one potential factor explaining the clustering of multiple metabolic risk factors including hypertension, obesity, insulin resistance and glucose intolerance. Microvascular dysfunction may increase not only peripheral vascular resistance and blood pressure, but may also decrease insulin-mediated glucose uptake in muscle. The present article summarizes some of the data concerning the role of microvascular dysfunction in the metabolic syndrome.

Integration of the metabolic and cardiovascular effects of exercise

Abstract: Most of the essays in this volume have adopted a reductionist approach and have focused on the biochemistry either in skeletal muscle or in the vascular wall. There is however a complex interaction between the biochemistry in the endothelium of the microvascular wall, the vascular smooth muscle and the skeletal muscle fibres involving signalling pathways in the three tissues and an intense exchange of signal molecules between them. In the present essay an integrative overview is given of this complex metabolic interaction and the impairments in it that lead to type 2 diabetes and cardiovascular disease.A reduced nitric oxide production by the (micro)vascular endothelium is identified as the key event and is reversible by regular exercise and a reduced calorie intake. The chapter also contains a description of the complex metabolic network controlled by the inducible transcription factor nuclear factor-kappaB, that is activated in more advanced stages of the chronic diseases, and either leads to repair of the microvascular wall or to irreversible damage and the severe complications of end stage cardiovascular disease and type 2 diabetes.

Exercise, genetics and prevention of type 2 diabetes.

Abstract: Type 2 diabetes is one of the fastest growing public health problems in both developed and developing countries. Cardiovascular disease is the most prevalent complication of type 2 diabetes. In the past decade, the associations of physical activity, physical fitness and changes in the lifestyle with the risk of type 2 diabetes have been assessed by a number of prospective studies and clinical trials. A few studies have also evaluated the joint associations of physical activity, body mass index and glucose levels with the risk of type~2 diabetes. The results based on prospective studies and clinical trials have shown that moderate or high levels of physical activity or physical fitness and changes in the lifestyle (dietary modification and increase in physical activity) can prevent type 2 diabetes.

Muscle metabolism and control of capillary blood flow: insulin and exercise.

Abstract: The evidence that muscle metabolism is determined by available capillary surface area is examined. From newly developed methods it is clear that exercise and insulin mediate capillary recruitment as part of their actions in vivo. In all insulin-resistant states examined thus far, insulin-mediated capillary recruitment is impaired with little or no change to the exercise response. Control mechanisms for capillary recruitment for exercise and insulin are considered, and the failure of the microvasculature to respond to insulin is examined for possible mechanisms that might account for impaired vascular responses to insulin in insulin resistance.