bluuebunny/crossref_metadata_2025 huggingface dataset:
Signalling components involved in contraction-inducible substrate uptake into cardiac myocytes
Authors: Luiken Joost J. F. P. , Coort Susan L. M. , Koonen Debby P. Y. , Bonen Arend , Glatz Jan F. C.
Published: August 2004

Glucose and long-chain fatty acids (LCFA) are two major substrates used by heart and skeletal muscle to support contractile activity. In quiescent cardiac myocytes a substantial portion of the glucose transporter GLUT4 and the putative LCFA transporter fatty acid translocase (FAT)/CD36 are stored in intracellular compartments. Induction of cellular contraction by electrical stimulation results in enhanced uptake of both glucose and LCFA through translocation of GLUT4 and FAT/CD36 respectively to the sarcolemma. The involvement of protein kinase A, AMP-activated protein kinase (AMPK), protein kinase C (PKC) isoforms and the extracellular signal-regulated kinases was evaluated in cardiac myocytes as candidate signalling enzymes involved in recruiting these transporters in response to contraction. The collected evidence excluded the involvement of PKA and implicated an important role for AMPK and for one (or more) PKC isoform(s) in contraction-induced translocation of both GLUT4 and FAT/CD36. The unravelling of further components along this contraction pathway can provide valuable information on the coordinated regulation of the uptake of glucose and of LCFA by an increase in mechanical activity of heart and skeletal muscle.
Involvement of PPARγ co-activator-1, nuclear respiratory factors 1 and 2, and PPARα in the adaptive response to endurance exercise
Authors: Baar Keith
Published: August 2004

Endurance exercise training induces an increase in the respiratory capacity of muscle, resulting in an increased capacity to generate ATP as well as improved efficiency of muscle contraction. Such adaptations are largely the result of a coordinated genetic response that increases mitochondrial proteins, fatty acid oxidation enzymes and the exercise- and insulin-stimulated glucose transporter GLUT4, and shifts the contractile and regulatory proteins to their more efficient isoforms. In recent years a number of the transcriptional regulators involved in this genetic response have been identified and these factors can be classified into two different groups. The first group comprises transcription factors such as nuclear respiratory factors (NRF) 1 and 2 and PPARα that bind DNA in a sequence-specific manner. The second group, referred to as transcriptional co-activators, alter transcription without directly binding to DNA. The PPARγ co-activator (PGC) family of proteins have been identified as the central family of transcriptional co-activators for induction of mitochondrial biogenesis. PGC-1α is activated by exercise, and is sufficient to produce the endurance phenotype through direct interactions with NRF-1 and PPARα, and potentially NRF-2. Furthering the understanding of the activation of PGC proteins following exercise has implications beyond improving athletic performance, including the possibility of providing targets for the treatment of frailty in the elderly, obesity and diseases such as mitochondrial myopathies and diabetes.
The role of calcium and calcium/calmodulin-dependent kinases in skeletal muscle plasticity and mitochondrial biogenesis
Authors: Chin Eva R.
Published: August 2004

Intracellular Ca2+plays an important role in skeletal muscle excitation–contraction coupling and also in excitation–transcription coupling. Activity-dependent alterations in muscle gene expression as a result of increased load (i.e. resistance or endurance training) or decreased activity (i.e. immobilization or injury) are tightly linked to the level of muscle excitation. Differential expression of genes in slow- and fast-twitch fibres is also dependent on fibre activation. Both these biological phenomena are, therefore, tightly linked to the amplitude and duration of the Ca2+transient, a signal decoded downstream by Ca2+-dependent transcriptional pathways. Evidence is mounting that the calcineurin–nuclear factor of activated T-cells pathway and the Ca2+/calmodulin-dependent kinases (CaMK) II and IV play important roles in regulating oxidative enzyme expression, mitochondrial biogenesis and expression of fibre-type specific myofibrillar proteins. CaMKII is known to decode frequency-dependent information and is activated during hypertrophic growth and endurance adaptations. Thus, it was hypothesized that CaMKII, and possibly CaMKIV, are down regulated during muscle atrophy and levels of expression of CaMKIIα, -IIβ, -IIγ and -IV were assessed in skeletal muscles from young, aged and denervated rats. The results indicate that CaMKIIγ, but not CaMKIIα or -β, is up regulated in aged and denervated soleus muscle and that CaMKIV is absent in skeletal but not cardiac muscle. Whether CaMKIIγ up-regulation is part of the pathology of wasting or a result of some adaptational response to atrophy is not known. Future studies will be important in determining whether insights from the adaptational response of muscle to increased loads will provide pharmacological approaches for increasing muscle strength or endurance to counter muscle wasting.
The biochemical basis of the health effects of exercise: an integrative view
Authors: Booth Frank W. , Andrew Shanely R.
Published: August 2004

Physical inactivity–gene interactions result in changes in gene expression, leading to phenotypic changes in the skeletal muscle cell. A subpopulation of those genes that show changes in expression during physical inactivity are candidates for the environment–gene interactions that cross a threshold of biological significance such that overt clinical disease occurs. AMP kinase, GLUT4 and myosin heavy chain IIx are proposed as candidates for physical inactivity-modulated genes that have an altered function that may trigger a crossing of a threshold to disease. Future experiments will be needed to test the validity of the ideas presented.
The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor?
Authors: Pedersen B. K. , Steensberg A. , Fischer C. , Keller C. , Keller P. , Plomgaard P. , Wolsk-Petersen E. , Febbraio M.
Published: August 2004

For most of the last century, researchers have searched for a muscle contraction-induced factor that mediates some of the exercise effects in other tissues such as the liver and the adipose tissue. It has been called the ‘work stimulus’, the ‘work factor’ or the ‘exercise factor’. In the search for such a factor, a cytokine, IL-6, was found to be produced by contracting muscles and released into the blood. It has been demonstrated that IL-6 has many biological roles such as: (1) induction of lipolysis; (2) suppression of TNF production; (3) stimulation of cortisol production. The IL-6 gene is rapidly activated during exercise, and the activation of this gene is further enhanced when muscle glycogen content is low. In addition, carbohydrate supplementation during exercise has been shown to inhibit the release of IL-6 from contracting muscle. Thus, it is suggested that muscle-derived IL-6 fulfils the criteria of an exercise factor and that such classes of cytokines could be termed ‘myokines’.
Role of calcium and AMP kinase in the regulation of mitochondrial biogenesis and GLUT4 levels in muscle
Authors: Ojuka Edward O.
Published: August 2004

Contractile activity induces mitochondrial biogenesis and increases glucose transport capacity in muscle. There has been much research on the mechanisms responsible for these adaptations. The present paper reviews the evidence, which indicates that the decrease in the levels of high-energy phosphates, leading to activation of AMP kinase (AMPK), and the increase in cytosolic Ca2+, which activates Ca2+/calmodulin-dependent protein kinase (CAMK), are signals that initiate these adaptative responses. Although the events downstream of AMPK and CAMK have not been well characterized, these events lead to activation of various transcription factors, including: nuclear respiratory factors (NRF) 1 and 2, which cause increased expression of proteins of the respiratory chain; PPAR-α, which up regulates the levels of enzymes of β oxidation; mitochondrial transcription factor A, which activates expression of the mitochondrial genome; myocyte-enhancing factor 2A, the transcription factor that regulates GLUT4 expression. The well-orchestrated expression of the multitude of proteins involved in these adaptations is mediated by the rapid activation of PPARγ co-activator (PGC) 1, a protein that binds to various transcription factors to maximize transcriptional activity. Activating AMPK using 5-aminoimidizole-4-carboxamide-1-β-D-riboside (AICAR) and increasing cytoplasmic Ca2+using caffeine, W7 or ionomycin in L6 myotubes increases the concentration of mitochondrial enzymes and GLUT4 and enhances the binding of NRF-1 and NRF-2 to DNA. AICAR and Ca-releasing agents also increase the levels of PGC-1, mitochondrial transcription factor A and myocyte-enhancing factors 2A and 2D. These results are similar to the responses seen in muscle during the adaptation to endurance exercise and show that L6 myotubes are a suitable model for studying the mechanisms by which exercise causes the adaptive responses in muscle mitochondria and glucose transport.
Regulation of glucose transport by the AMP-activated protein kinase
Authors: Fujii Nobuharu , Aschenbach William G. , Musi Nicolas , Hirshman Michael F. , Goodyear Laurie J.
Published: August 2004

The AMP-activated protein kinase (AMPK) is an energy-sensing enzyme that is activated during exercise and muscle contraction as a result of acute decreases in ATP:AMP and phosphocreatine:creatine. Physical exercise increases muscle glucose uptake, enhances insulin sensitivity and leads to fatty acid oxidation in muscle. An important issue in muscle biology is to understand whether AMPK plays a role in mediating these metabolic processes. AMPK has also been implicated in regulating gene transcription and, therefore, may function in some of the cellular adaptations to training exercise. Recent studies have shown that the magnitude of AMPK activation and associated metabolic responses are affected by factors such as glycogen content, exercise training and fibre type. There have also been conflicting reports as to whether AMPK activity is necessary for contraction-stimulated glucose transport. Thus, during the next several years considerably more research will be necessary in order to fully understand the role of AMPK in regulating glucose transport in skeletal muscle.
New concepts of cellular fatty acid uptake: role of fatty acid transport proteins and of caveolae
Authors: Pohl Jürgen , Ring Axel , Herrmann Thomas , Stremmel Wolfgang
Published: August 2004

Efficient uptake and channelling of long-chain fatty acids (LCFA) are critical cell functions. Evidence is emerging that proteins are important mediators of LCFA-trafficking into cells and various proteins have been suggested to be involved in this process. Amongst these proteins is a family of membrane-associated proteins termed fatty acid transport proteins (FATP). So far six members of this family, designated FATP 1–6, have been characterized. FATP 1, 2 and 6 show a highly-conserved AMP-binding region that participates in the activation of very-long-chain fatty acids (VLCFA) to form their acyl-CoA derivatives. The mechanisms by which FATP mediate LCFA uptake are not well understood, but several studies provide evidence that uptake of LCFA across cellular membranes is closely linked to acyl-CoA synthetase activity. It is proposed that FATP indirectly enhance LCFA uptake by activating VLCFA to their CoA esters, which are required to maintain the typical structure of lipid rafts in cellular membranes. Recent work has shown that the structural integrity of lipid rafts is essential for cellular LCFA uptake. This effect might be exerted by proteins, e.g. caveolin-1 and FAT/CD36, that use lipid rafts as platforms and bind or transport LCFA. The proposed molecular mechanisms await further experimental investigation.
Mitochondrial assembly: protein import
Authors: Hood David A. , Joseph Anna-Maria
Published: August 2004

The protein import process of mitochondria is vital for the assembly of the hundreds of nuclear-derived proteins into an expanding organelle reticulum. Most of our knowledge of this complex multisubunit network comes from studies of yeast and fungal systems, with little information known about the protein import process in mammalian cells, particularly skeletal muscle. However, growing evidence indicates that the protein import machinery can respond to changes in the energy status of the cell. In particular, contractile activity, a powerful inducer of mitochondrial biogenesis, has been shown to alter the stoichiometry of the protein import apparatus via changes in several protein import machinery components. These adaptations include the induction of cytosolic molecular chaperones that transport precursors to the matrix, the up-regulation of outer membrane import receptors, and the increase in matrix chaperonins that facilitate the import and proper folding of the protein for subsequent compartmentation in the matrix or inner membrane. The physiological importance of these changes is an increased capacity for import into the organelle at any given precursor concentration. Defects in the protein import machinery components have been associated with mitochondrial disorders. Thus, contractile activity may serve as a possible mechanism for up-regulation of mitochondrial protein import and compensation for mitochondrial phenotype alterations observed in diseased muscle.
Exercise signalling to glucose transport in skeletal muscle
Authors: Richter Erik A. , Nielsen Jakob N. , Jørgensen Sebastian B. , Frøsig Christian , Birk Jesper B. , Wojtaszewski Jørgen F. P.
Published: August 2004

Contraction-induced glucose uptake in skeletal muscle is mediated by an insulin-independent mechanism that leads to translocation of the GLUT4 glucose transporter to the muscle surface membrane from an intracellular storage site. Although the signalling events that increase glucose transport in response to muscle contraction are not fully elucidated, the aim of the present review is to briefly present the current understanding of the molecular signalling mechanisms involved. Glucose uptake may be regulated by Ca2+-sensitive contraction-related mechanisms, possibly involving Ca2+/calmodulin-dependent protein kinase II and some isoforms of protein kinase C. In addition, glucose transport may be regulated by mechanisms that reflect the metabolic status of the muscle, probably involving the 5′AMP-activated protein kinase. Furthermore, the p38 mitogen-activated protein kinase may be involved in activating the GLUT4 translocated to the surface membrane. Nevertheless, the picture is incomplete, and fibre type differences also seem to be involved.
Muscle glycogen and metabolic regulation
Authors: Hargreaves Mark
Published: August 2004

Muscle glycogen is an important fuel for contracting skeletal muscle during prolonged strenuous exercise, and glycogen depletion has been implicated in muscle fatigue. It is also apparent that glycogen availability can exert important effects on a range of metabolic and cellular processes. These processes include carbohydrate, fat and protein metabolism during exercise, post-exercise glycogen resynthesis, excitation–contraction coupling, insulin action and gene transcription. For example, low muscle glycogen is associated with reduced muscle glycogenolysis, increased glucose and NEFA uptake and protein degradation, accelerated glycogen resynthesis, impaired excitation–contraction coupling, enhanced insulin action and potentiation of the exercise-induced increases in transcription of metabolic genes. Future studies should identify the mechanisms underlying, and the functional importance of, the association between glycogen availability and these processes.
Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise
Authors: Pilegaard Henriette , Darrell Neufer P.
Published: August 2004

The pyruvate dehydrogenase complex (PDC) has a key position in skeletal muscle metabolism as it represents the entry of carbohydrate-derived fuel into the mitochondria for oxidation. PDC is regulated by a phosphorylation–dephosphorylation cycle, in which the pyruvate dehydrogenase kinase (PDK) phosphorylates and inactivates the complex. PDK exists in four isoforms, of which the PDK4 isoform is predominantly expressed in skeletal and heart muscle. PDK4 transcription and PDK4 mRNA are markedly increased in human skeletal muscle during prolonged exercise and after both short-term high-intensity and prolonged low-intensity exercise. The exercise-induced transcriptional response of PDK4 is enhanced when muscle glycogen is lowered before the exercise, and intake of a low-carbohydrate high-fat diet during recovery from exercise results in increased transcription and mRNA content of PDK4 when compared with intake of a high-carbohydrate diet. The activity of pyruvate dehydrogenase (PDH) is increased during the first 2 h of low-intensity exercise, followed by a decrease towards resting levels, which is in line with the possibility that the increased PDK4 expressed influences the PDH activity already during prolonged exercise. PDK4 expression is also increased in response to fasting and a high-fat diet. Thus, increased PDK4 expression when carbohydrate availability is low seems to contribute to the sparing of carbohydrates by preventing carbohydrate oxidation. The impact of substrate availability on PDK4 expression during recovery from exercise also underlines the high metabolic priority given to replenishing muscle glycogen stores and re-establishing intracellular homeostasis after exercise.
Exercise-induced mitogen-activated protein kinase signalling in skeletal muscle
Authors: Chau Long Yun , Widegren Ulrika , Zierath Juleen R.
Published: August 2004

Exercise training improves glucose homeostasis through enhanced insulin sensitivity in skeletal muscle. Muscle contraction through physical exercise is a physiological stimulus that elicits multiple biochemical and biophysical responses and therefore requires an appropriate control network. Mitogen-activated protein kinase (MAPK) signalling pathways constitute a network of phosphorylation cascades that link cellular stress to changes in transcriptional activity. MAPK cascades are divided into four major subfamilies, including extracellular signal-regulated kinases 1 and 2, p38 MAPK, c-Jun NH2-terminal kinase and extracellular signal-regulated kinase 5. The present review will present the current understanding of parallel MAPK signalling in human skeletal muscle in response to exercise and muscle contraction, with an emphasis on identifying potential signalling mechanisms responsible for changes in gene expression.
Intramyocellular triacylglycerol as a substrate source during exercise
Authors: van Loon Luc J. C.
Published: August 2004

The role of intramyocellular triacylglycerol (IMTG) as a substrate source during exercise has recently regained much attention as a result of the proposed functional relationship between IMTG accumulation and the development of insulin resistance. It has been speculated that elevated NEFA delivery and/or impaired fatty acid (FA) oxidation result in intramyocellular accumulation of triacylglycerol and FA metabolites, which are likely to induce defects in the insulin signalling cascade, causing insulin resistance. The progressive accumulation of IMTG in sedentary patients and patients who are obese and/or have type 2 diabetes should therefore form a major therapeutic target, and efforts should be made to develop interventions that prevent excess IMTG accretion by stimulating their rate of oxidation. Although regular exercise is likely to represent such an effective means, there is much controversy about the actual contribution of the IMTG pool as a substrate source during exercise. The apparent discrepancy in the published literature might be explained by differences in the applied research protocol and the selected subject population, but most of all by the techniques that have been employed to estimate IMTG use during exercise. Data obtained in trained-endurance athletes indicate that athletes can substantially reduce their IMTG pool following a single exercise session. With the growing awareness that skeletal muscle has a tremendous potential to oxidise IMTG during prolonged moderate-intensity exercise, more research is warranted to develop combined exercise, nutritional and/or pharmacological interventions that can stimulate IMTG oxidation in sedentary patients and patients who are obese and/or have type 2 diabetes.
Regulation of glycogen synthase activity and phosphorylation by exercise
Authors: Nielsen Jakob N. , Wojtaszewski Jørgen F. P.
Published: August 2004

Glycogen synthase (GS) catalyses the rate-limiting step of UDP-glucose incorporation into glycogen. Exercise is a potent regulator of GS activity, leading to activation of GS immediately after exercise promoting glycogen repletion by mechanisms independent of insulin. The incorporation of UDP-glucose is energy demanding, and during intense exercise GS is deactivated, diminishing energy utilization but also increasing the potential for glycogen breakdown. An apparent activation of GS is observed during moderate exercise, which could be considered as a potential waste of energy, although the cellular capacity for glycogen breakdown is considerably higher than that for glycogen synthesis. The understanding of this complex regulation of GS activity in response to exercise is just at its beginning. In the present review potential mechanisms by which exercise regulates GS activity are described, factors that may promote GS activation and factors that may deactivate GS are discussed, pointing to the view that GS activity during exercise is the result of the relative strength of these opposing factors.
Metabolic flexibility
Authors: Storlien Len , Oakes Nick D. , Kelley David E.
Published: August 2004

Human physiology needs to be well adapted to cope with major discontinuities in both the supply of and demand for energy. This adaptability requires ‘a clear capacity to utilize lipid and carbohydrate fuels and to transition between them’ ( Kelley et al. 2002b). Such capacities characterize the healthy state and can be termed ‘metabolic flexibility’. However, increasing evidence points to metabolic inflexibility as a key dysfunction of the cluster of disease states encompassed by the term ‘metabolic syndrome’. In obese and diabetic individuals this inflexibility is manifest in a range of metabolic pathways and tissues including: (1) failure of cephalic-phase insulin secretion (impaired early-phase prandial insulin secretion concomitant with failure to suppress hepatic glucose production and NEFA efflux from adipose tissue); (2) failure of skeletal muscle to appropriately move between use of lipid in the fasting state and use of carbohydrate in the insulin-stimulated prandial state; (3) impaired transition from fatty acid efflux to storage in response to a meal. Finally, it is increasingly clear that reduced capacity for fuel usage in, for example, skeletal muscle, as indicated by reduced mitochondrial size and density, is characteristic of the metabolic syndrome state and a fundamental component of metabolic inflexibility. Key questions that remain are how metabolic flexibility is lost in obese and diabetic individuals and by what means it may be regained.
Physiological regulation of NEFA availability: lipolysis pathway
Authors: Stich V. , Berlan M.
Published: August 2004

Plasma NEFA are an important energy substrate and, furthermore, play a key role in the induction of insulin resistance in the body. The availability of NEFA is determined predominantly by their mobilization from adipose tissue triacylglycerol stores by the process of lipolysis. Adipose tissue lipolysis in man is regulated by a number of hormonal and paracrine and/or autocrine signals. The main hormonal signals may be represented by catecholamines, insulin, growth hormone, natriuretic peptides and some adipocytokines. The absolute levels and relative importance and contribution of these signals vary in different physiological situations, with diet and physical exercise being the main physiological variables that affect the hormonal signalling. Thus, modulations in hormonal signals induce an increase in NEFA mobilization in the post-absorptive state and during an acute bout of exercise, and suppress NEFA mobilization in the postprandial state. In addition, hormonal regulation is modified by long-term interventions in energy balance, such as dietary restriction and/or physical training, and is disturbed in some pathological states, such as obesity or diabetes. The question that remains is whether disturbances in lipolysis regulation in obese and diabetic subjects may be ‘corrected’ by the long-term interventions in diet and physical activity.
The molecular mechanism linking muscle fat accumulation to insulin resistance
Authors: Hulver Matthew W. , Lynis Dohm G.
Published: August 2004

Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport.
Physical activity and health, novel concepts and new targets: report from the 12th Conference of the International Research Group on the Biochemistry of Exercise
Authors: Hesselink Matthijs K. C. , van Baak Marleen A.
Published: August 2004

The present paper is the introductory paper to a series of brief reviews representing the proceedings of a recent conference on ‘The biochemical basis for the health effects of exercise’ organized by the International Research Group on the Biochemistry of Exercise in conjunction with the Nutrition Society. Here the aim is to briefly review and highlight the main innovations presented during this meeting. The following topics were covered during the meeting: exercise signalling pathways controlling fuel oxidation during and after exercise; the fatty acid transporters of skeletal muscle; mechanisms involved in exercise-induced mitochondrial biogenesis in skeletal muscle; new methodologies and insights in the regulation of fat metabolism during exercise; muscle hypertrophy: the signals of insulin, amino acids and exercise; adipose tissue–liver–muscle interactions leading to insulin resistance. In these symposia state-of-the-art knowledge on how physical exercise exerts its effects on health was presented. The fast-growing number of identified pathways and processes involved in the health effects of physical exercise, which were discussed during the meeting, will help to develop tailored physical-activity regimens in the prevention of inactivity-induced deterioration of health.
Insulin-like growth factor 1 and muscle growth: implication for satellite cell proliferation
Authors: Machida Shuichi , Booth Frank W.
Published: August 2004

Insulin-like growth factor 1 (IGF-1) has been shown to rescue the aging-related or inactivity-induced loss of muscle mass through the activation of satellite cells. However, the signalling pathways and the mechanism by which IGF-1 affects satellite cells have not been not completely identified. The purpose of the present review is to provide current understanding of the cellular and molecular events underlying IGF-1 induced proliferation of satellite cells.
Regulation of protein synthesis associated with skeletal muscle hypertrophy by insulin-, amino acid- and exercise-induced signalling
Authors: Bolster Douglas R. , Jefferson Leonard S. , Kimball Scot R.
Published: August 2004

Although insulin, amino acids and exercise individually activate multiple signal transduction pathways in skeletal muscle, one pathway, the phosphatidylinositol 3-kinase (PI3K)–mammalian target of rapamycin (mTOR) signalling pathway, is a target of all three. Activation of the PI3K–mTOR signal transduction pathway results in both acute (i.e. occurring in minutes to hours) and long-term (i.e. occurring in hours to days) up-regulation of protein synthesis through modulation of multiple steps involved in mediating the initiation of mRNA translation and ribosome biogenesis respectively. In addition, changes in gene expression through altered patterns of mRNA translation promote cell growth, which in turn promotes muscle hypertrophy. The focus of the present discussion is to review current knowledge concerning the mechanism(s) through which insulin, amino acids and resistance exercise act to activate the PI3K–mTOR signal transduction pathway and thereby enhance the rate of protein synthesis in muscle.
Metabolic and hormonal interactions between muscle and adipose tissue
Authors: Tomas Eva , Kelly Meghan , Xiang Xiaoqin , Tsao Tsu-Shuen , Keller Charlotte , Keller Pernille , Luo Zhijun , Lodish Harvey , Saha Asish K. , Unger Roger , Ruderman Neil B.
Published: August 2004

From the perspective of a muscle physiologist, adipose tissue has long been perceived predominantly as a fuel reservoir that provides muscle and other tissues with NEFA when exogenous nutrients are insufficient for their energy needs. Recently, studies have established that adipose tissue is also an endocrine organ. Among the hormones it releases are adiponectin and leptin, both of which can activate AMP-activated protein kinase and increase fatty acid oxidation in skeletal muscle and probably other tissues. Deficiencies of leptin or leptin receptor, adiponectin and IL-6 are associated with obesity, insulin resistance and a propensity to type 2 diabetes. In addition, a lack of adiponectin has been linked to atherosclerosis. Whether this pathology reflects a deficient activation of AMP-activated protein kinase in peripheral tissues remains to be determined. Finally, recent studies have suggested that skeletal muscle may also function as an endocrine organ when it releases the cytokine IL-6 into the circulation during sustained exercise. Interestingly, one of the apparent effects of IL-6 is to stimulate lipolysis, causing the release of NEFA from the adipocyte. Thus, hormonal communications exist between the adipocyte and muscle that could enable them to talk to each other. The physiological relevance of this cross talk clearly warrants further study.
Mechanotransduction and the regulation of protein synthesis in skeletal muscle
Authors: Hornberger T. A. , Esser K. A.
Published: August 2004

Repeated bouts of resistance exercise produce an increase in skeletal muscle mass. The accumulation of protein associated with the growth process results from a net increase in protein synthesis relative to breakdown. While the effect of resistance exercise on muscle mass has long been recognized, the mechanisms underlying the link between high-resistance contractions and the regulation of protein synthesis and breakdown are, to date, poorly understood. In the present paper skeletal muscle will be viewed as a mechanosensitive cell type and the possible mechanisms through which mechanically-induced signalling events lead to changes in rates of protein synthesis will be examined.
Regulation and role of hormone-sensitive lipase in rat skeletal muscle
Authors: Donsmark Morten , Langfort Jozef , Holm Cecilia , Ploug Thorkil , Galbo Henrik
Published: August 2004

Intramyocellular triacylglycerol (TG) is an important energy store, and the energy content of this depot is higher than the energy content of the muscle glycogen depot. It has recently been shown that the mobilization of fatty acids from this TG pool may be regulated by the neutral lipase hormone-sensitive lipase (HSL). This enzyme is known to be rate limiting for intracellular TG hydrolysis in adipose tissue. The presence of HSL has been demonstrated in all muscle fibre types by Western blotting of muscle fibres isolated by collagenase treatment or after freeze-drying. The content of HSL varies between fibre types, being higher in oxidative fibres than in glycolytic fibres. When analysed under conditions optimal for“ HSL, neutral lipase activity in muscle can be stimulated by adrenaline as well as by contractions. These increases are abolished by the presence of anti-HSL antibody during analysis. Moreover, immunoprecipitation with affinity-purified anti-HSL antibody causes similar reductions in muscle HSL protein concentration and in measured neutral lipase responses to contractions. The immunoreactive HSL in muscle is stimulated by adrenaline via β-adrenergic activation of cAMP-dependent protein kinase (PKA). From findings in adipocytes it is likely that PKA phosphorylates HSL at residues Ser563, Ser659and Ser660. Contraction probably also enhances muscle HSL activity by phosphorylation, because the contraction-induced increase in HSL activity is elevated by the protein phosphatase inhibitor okadaic acid and reversed by alkaline phosphatase. A novel signalling pathway in muscle by which HSL activity may be stimulated by protein kinase C (PKC) via extracellular signal-regulated kinase (ERK) has been demonstrated. In contrast to previous findings in adipocytes, in muscle the activation of ERK is not necessary for stimulation of HSL by adrenaline. However, contraction-induced HSL activation is mediated by PKC, at least partly via the ERK pathway. In fat cells ERK is known to phosphorylate HSL at Ser600. Hence, phosphorylation of different sites may explain the finding that in muscle the effects of contractions and adrenaline on HSL activity are partially additive. In line with the view that the two stimuli act by different mechanisms, training increases contraction-mediated HSL activation but diminishes adrenaline-mediated HSL activation in muscle. In conclusion, HSL is present in skeletal muscle and can be activated by phosphorylation in response to both adrenaline and muscle contractions. Training increases contraction-mediated HSL activation, but decreases adrenaline-mediated HSL activation in muscle.
Regulation and role of hormone-sensitive lipase activity in human skeletal muscle
Authors: Watt Matthew J. , Spriet Lawrence L.
Published: August 2004

Hormone-sensitive lipase (HSL) is believed to play a regulatory role in initiating the degradation of intramuscular triacylglycerol (IMTG) in skeletal muscle. A series of studies designed to characterise the response of HSL to three stimuli: exercise of varying intensities and durations; adrenaline infusions; altered fuel supply have recently been conducted in human skeletal muscle. In an attempt to understand the regulation of HSL activity the changes in the putative intramuscular and hormonal regulators of the enzyme have also been measured. In human skeletal muscle at rest there is a high constitutive level of HSL activity, which is not a function of biopsy freezing. The combination of low adrenaline and Ca2+levels and resting levels of insulin appear to dictate the level of HSL activity at rest. During the initial minute of low and moderate aerobic exercise HSL is activated by contractions in the apparent absence of increases in circulating adrenaline. During intense aerobic exercise, adrenaline may contribute to the early activation of HSL. The contraction-induced activation may be related to increased Ca2+and/or other unknown intramuscular activators. As low- and moderate-intensity exercise continues beyond a few minutes, activation by adrenaline through the cAMP cascade may also occur. With prolonged moderate-intensity exercise beyond 1–2 h and sustained high-intensity exercise, HSL activity decreases despite continuing increases in adrenaline, possibly as a result of increasing accumulations of free AMP, activation of AMP kinase and phosphorylation of inhibitory sites on HSL. The existing work in human skeletal muscle also suggests that there are numerous levels of control involved in the regulation of IMTG degradation, with control points downstream from HSL also being important. For example, it must be remembered that the actual flux (IMTG degradation) through HSL may be allosterically inhibited during prolonged exercise as a result of the accumulation of long-chain fatty acyl-CoA.
Basic disturbances in skeletal muscle fatty acid metabolism in obesity and type 2 diabetes mellitus
Authors: Blaak E. E.
Published: August 2004

The present article addresses the hypothesis that disturbances in skeletal muscle fatty acid handling in abdominal obesity and type 2 diabetes mellitus may play a role in the aetiology of increased adipose tissue stores, increased triacylglycerol storage in skeletal muscle and skeletal muscle insulin resistance. The uptake and/or oxidation of fatty acids have been shown to be impaired during post-absorptive conditions in abdominally-obese subjects and/or subjects with type 2 diabetes. Also, human studies have shown that muscle of subjects that are (abdominally) obese and/or have type 2 diabetes is characterized by an inability to increase fatty acid uptake and/or fatty acid oxidation during β-adrenergic stimulation and exercise. This disturbance in fat oxidation may promote, on one hand, the development of increased adipose tissue stores and obesity. On the other hand, fatty acids that are taken up by muscle and not oxidized may increase triacylglycerol storage in muscle, which has been associated with skeletal-muscle insulin resistance. Disturbances in the capacity to increase fat oxidation during post-absorptive conditions, β-adrenergic stimulation and exercise in subjects who are obese and/or have type 2 diabetes persist after weight reduction, indicating that the diminished fat oxidation may be a primary factor leading to the obese and/or insulin-resistant state rather than an adaptational response. Clearly, the precise sequence of events leading to an increased adiposity and insulin resistance in obesity and type 2 diabetes mellitus is not yet fully understood.
Calcineurin and skeletal muscle growth
Authors: Michel Robin N. , Dunn Shannon E. , Chin Eva R.
Published: August 2004

Recruitment determines the profile of fibre-type-specific genes expressed across the range of muscle fibres associated with slow, fast fatigue-resistant and fast fatiguable motor units. Downstream signalling pathways activated by neural signalling and mechanical load have been the focus of intensive research in past years. It is now known that Ca2+-dependent calcineurin–nuclear factor of activated T cells and insulin-like growth factor 1 pathways and their downstream mediators contribute to these adaptive responses. These pathways regulate gene expression through muscle-specific (myocyte-enhancing factor 2, myoblast determination protein) and non-specific (nuclear factor of activated T cell 2, GATA-2) transcription factors. Transcriptional signals activated with increased contractile activity result in altered expression of fibre-type specific genes, including the myosin heavy chain isoforms and oxidative and glycolytic enzymes and a net change in muscle fibre-type composition. In contrast, transcriptional signals activated by increased load bearing result in hypertrophy or a growth response, a component of which involves satellite cell recruitment and fusion with existing adult myofibres. Calcineurin has been identified as a key mediator in the hypertrophic response, and the current challenge has been to determine the downstream target genes of this pathway. Exciting new data have emerged, showing that myostatin, a negative regulator of muscle growth, and utrophin, a cytoskeletal protein important in maintaining membrane integrity, are downstream targets of calcineurin signalling. Increased understanding of these mediators of muscle growth may provide strategies for the development of effective therapeutics to counter muscle weakness and muscular dystrophy.
Space, Risk and Opportunity: The Evolution of Paid Sex Markets
Authors: Cameron Samuel
Published: August 2004

The emergence of paid sex markets is a product of various locational economies. By this it is meant that coherent paid sex markets are intimately linked with various economies of agglomeration, synergy, complementarity and 'laddering' whereby an entrant to paid sex consumption may progress from low intimacy/low value added products to those of higher intimacy/higher value added. Physical clustering of traded sex commodities can also enhance the progression of the consumer's ladder by heightening the stimulus to enter such markets for the first time. This paper discusses the above factors in the context of the economic theory of clubs with particular reference to the use of zoning ordinances to control the location of adult entertainment providers.
Urban Space and Homosexuality: The Example of the Marais, Paris' 'Gay Ghetto'
Authors: Sibalis Michael
Published: August 2004

'Gay ghettos'—neighbourhoods dominated by homosexual men and women-have emerged during recent decades in many cities in North America and western Europe, including in Paris' historical Marais quarter. The gay Marais resulted from economic and social factors such as initially low rents and real-estate prices in a run-down neighbourhood ripe for gentrification, a central location with good public transport and the emergence of an urban gay community eager to establish a territorial base for its political militancy. In addition, gay businessmen consciously set out to establish commercial venues in the Marais that would embody a more openly gay lifestyle. The Marais and this lifestyle have become objects of bitter attack from both outside and within the gay community. Residents resent the intrusion into their neighbourhood, while others denounce the formation of a distinct gay identity as 'communitarianism' and a threat to French national values.
Where Love Dares (Not) Speak Its Name: The Expression of Homosexuality in Singapore
Authors: Lim Kean Fan
Published: August 2004

Adopting Henri Lefebvre's spatial conceptual triad, this paper provides a critical investigation into the socio-spatial expression of homosexuality in Singapore. It explores how social space is not ontological, but constructed and reinforced as heterosexual. Specifically, an analysis is made of the roles of statistics, educational content and legal tools in fortifying heteronormativity. However, this paper contends that homosexuals in Singapore are not merely passive subjects entirely dominated by heterosexual norms/regulations. They have demonstrated, through subtle strategies of overt expressions in public spaces, that they are conscious and creative agents who are able to contest the heteronormative milieu in which they live. This is exemplified by the successful organisation of the 'Nation' party by homosexuals in the past three years and the rise in artistic expressions of homosexual-related themes/issues. Of course, the extent to which homosexuals are allowed to transgress heterosexual norms remains contingent on dominant (heterosexual) actors, and the paper critically interrogates why they have been allowed more space to do so in recent years.
Authenticating Queer Space: Citizenship, Urbanism and Governance
Authors: Bell David , Binnie Jon
Published: August 2004

The focus of this paper is the impact of the 'new urban order' on sexualised spaces in cities. The paper explores how sexual 'others' are conscripted into the process of urban transformation and, by turn, how city branding has become part of the sexual citizenship agenda. The interweaving of urban governance and sexual citizenship agendas produces particular kinds of sexual spaces, at the exclusion of other kinds. The paper considers the extent to which the idea of sexual citizenship has been woven into the tournament of urban entrepreneurialism and how this affects sexualised spaces. This process is read as an instance of 'the new homonormativity', producing a global repertoire of themed gay villages, as cities throughout the world weave commodified gay space into their promotional campaigns.
Sexuality and Sexual Services in the Urban Economy and Socialscape: An Overview
Authors: Collins Alan
Published: August 2004

Drawing primarily on some concepts in social theory, sociobiological reasoning and neo-classical economics, this paper provides an introductory overview to a collection of papers on an urban sexual theme. The papers address this theme from a wide variety of disciplinary perspectives and each contribution examines various facets and dimensions of the interplay of sexual desire and urban living. A simple conceptual model is offered to provide some guiding framework to the discourse on urban sexual consumption, which is a central feature of this brief overview commentary and also of the entire collection of papers. A number of research gaps and suggestions, that may help further to advance this research agenda, are then highlighted for possible future attention.
Local Elections in Independent Ukraine: The Case Study of Nikolayev*
Authors: Yatsunska Olena
Published: August 2004

In the current situation of societal modernization and transformation of the political system of Ukraine, one of the most important problems facing the country is the formation of a system of local self-government that can act effectively. If this institution is not developed and strengthened, there can be no discussion of the establishment of democratic, social government, of the development of the rule of law, or of an expansion of the infrastructure of civil society.
Fertility, Families and Ethnic Conflict: Macedonians and Albanians in the Republic of Macedonia, 1944–2002*
Authors: Brunnbauer Ulf
Published: August 2004

In 2001, the Republic of Macedonia—the former Yugoslavia's southernmost republic—was on the brink of civil war as the ethnic Albanian “National Liberation Army” (UÇK) was fighting Macedonian security forces and establishing rebel control over parts of the country. The armed conflict took more than 200 lives and displaced, at one time or another, more than 100,000 people. Civil war was prevented by an agreement between the four major ethnic Macedonian and ethnic Albanian parties in the country, signed on August 11, 2001 in the town of Ohrid, thereafter usually referred to as the “Ohrid Agreement.” Far-reaching constitutional and legislative changes would re-construct the Republic of Macedonia as a multi-ethnic democracy. Since then, constitutional amendments and new laws have been passed, increasing the rights and power of minorities, especially the Albanian one. The new constitution combines the concept of civic citizenship with elements ofde factoconsociationalism, and satisfies the demand of the Albanian minority to help shape the destiny of their country using a collective voice.