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Cibely Cristine Fontes-Oliveira,
Sílvia Busquets, Gemma Fuster,
Elisabet Ametller,
Maite Figueras,
Mireia Olivan,
Míriam Toledo,
Francisco J López-Soriano,
Xiaoyan Qu,
Jeffrey Demuth,
Paula Stevens,
Alex Varbanov,
Feng Wang,
Robert J Isfort,
Josep M Argilés
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ABSTRACT: BACKGROUND: Cachexia is a wasting condition that manifests in several types of cáncer. The main characteristic is a profound loss of muscle mass. METHODS: By using a micro-array system, the expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia-inducing tumor, the Yoshida AH-130 ascites hepatoma. This model induced a strong decrease in muscle mass in the tumor-bearing animals, as compared with their healthy counterparts. RESULTS: The results show important differences in gene expression in EDL skeletal muscle between tumor-bearing animals suffering from cachexia and control animals. CONCLUSIONS: The differences concern genes related to intracellular calcium homeostasis and genes involved in the control of mitochondrial oxidative phosphorylation and protein turnover, both at the level of protein synthesis and proteolysis. The stated differences may represent a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome. © 2013 Wiley Periodicals, Inc.
Muscle & Nerve 05/2013; · 2.37 Impact Factor
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ABSTRACT: Interleukin-15 (IL-15) is an anabolic factor for skeletal muscle and several reports have described its important role as a regulator of energy homeostasis. In this study, we analyzed the effects of IL-15 on adipocyte differentiation using the 3T3-L1 preadipose cell line. The data show that IL-15 tends to reduce the rate of adipocyte proliferation, induces apoptosis, and partially stops differentiation. The signaling molecules behind these actions of the cytokine on adipose cells are: p42/p44 MAPK (which seem to be associated with the reduced rate of proliferation induced by the cytokine), STAT5 (which is related to the actions of IL-15 on differentiation), and SAPK/JNK (which are related to the increased apoptosis induced by IL-15). In conclusion, using the 3T3-L1 adipocyte cell line, the results presented here show that IL-15 exerts important effects on differentiation, proliferation and apoptosis. Altogether, the results presented here reinforce the idea that IL-15 is an important mediator that regulates adipose size and, therefore, the role of the cytokine in affecting body weight and obesity deserves additional studies.
Lipids 09/2011; 46(11):1033-42. · 2.13 Impact Factor
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ABSTRACT: Proteolysis in skeletal muscle is mainly carried out by the activity of the ubiquitin-dependent proteolytic system. For the study of protein degradation through the ubiquitin-proteasome pathway, we used a model of hyperthermia in murine myotubes. In C2C12 cells, hyperthermia (41°C) induced a significant increase in both the rate of protein synthesis (18%) and degradation (51%). Interestingly, the addition of the β(2) -adrenoceptor agonist formoterol resulted in a significant decrease in protein degradation (21%) without affecting protein synthesis. The decrease in proteolytic rate was associated with decreases in gene expression of the different components of the ubiquitin-dependent proteolytic system. The effects of the β(2) -agonist on protein degradation were dependent exclusively on cAMP formation, because inhibition of adenylyl cyclase completely abolished the effects of formoterol on protein degradation. It can be concluded that hyperthermia is a suitable model for studying the anti-proteolytic potential of drugs used in the treatment of muscle wasting.
Muscle & Nerve 02/2011; 43(2):268-73. · 2.37 Impact Factor
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Josep M Argilés,
Cibely Cristine Fontes-Oliveira, Gemma Fuster,
Elisabet Ametller,
Maite Figueras,
Mireia Olivan,
Francisco J Lopez-Soriano,
Xiaoyan Qu,
Jeffrey Demuth,
Paula Stevens,
Alex Varbanov,
Feng Wang,
Robert J Isfort,
Sílvia Busquets
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ABSTRACT: The hypothesis we tested was that administering corticotropin-releasing factor receptor agonists preserves muscle mass during cancer that is related to changes in tissue gene expression. cDNA microarrays were used to compare mRNAs from muscle and adipose tissues of non-treated and agonist-treated tumor-bearing rats. In muscle of non-tumor-bearing agonist-treated animals we observed decreased expression of genes associated with fatty acid uptake and esterification. In tumor-bearing animals, CRF2R agonist administration produced decreased mRNA content of the atrogene lipin-1. In white adipose tissue, agonist treatment of non-tumor-bearing animals induced genes typically related to muscle structure and function. The fact that this treatment decreased expression of atrogenes could have clinical application. In addition, agonist treatment changed the gene pattern of adipose tissue to render it similar to that of skeletal muscle; thus, treatment with this agonist alters the gene pattern to what could be called "muscularization of white adipose tissue."
Muscle & Nerve 12/2010; 42(6):936-49. · 2.37 Impact Factor
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ABSTRACT: Different studies have revealed that the Ca2+-dependent serine/threonine phosphatase calcineurin is involved in the regulation of adipocyte differentiation. Calcineurin acts as a Ca2+-dependent molecular switch that negatively regulates the ability of 3T3-L1 cells to undergo adipocyte differentiation by preventing the expression of critical proadipogenic transcription factors. In this study we investigated the role of interleukin-15 (IL-15), a cytokine previously known to be involved in the control of fat accretion by adipose cells, in the differentiation of the 3T3-L1 preadipose cell line. We found that IL-15 is able to increase alpha-calcineurin mRNA content in white adipose tissue of rats chronically treated with the cytokine and also in the 3T3-L1 preadipose cell line. Moreover, IL-15 promoted a decrease in both leptin mRNA expression and lipid accumulation, as estimated by Red Oil O staining. Cotreatment with IL-15 and FK506 (a calcineurin inhibitor) resulted in no changes in lipid content compared with the non-treated group. These data suggest that IL-15 directly inhibits adipogenesis, possibly by upregulating alpha-calcineurin and preventing the induction of adipocyte differentiation.
International Journal of Molecular Medicine 11/2009; 24(4):453-8. · 1.98 Impact Factor
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ABSTRACT: C2C12 cells exposed to hyperthermia (41 degrees C) experienced an increase in both protein synthesis and degradation. The addition of IL15 under hyperthermic conditions resulted in an important increase in protein synthesis with no changes in protein degradation, except when cells overexpressed PPARdelta. The PPARdelta agonist GW501516 exerted similar effects on protein synthesis to IL15. Expression of a mutant dominant negative form of PPARdelta prevented the effect of the cytokine on protein synthesis, suggesting that this transcription factor is involved in the anabolic action of IL15. The present study also suggests that the effects of IL15 on lipid oxidation could be mediated by PPARdelta.
International Journal of Molecular Medicine 08/2009; 24(1):63-8. · 1.98 Impact Factor
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ABSTRACT: Interleukin-15 (IL-15) plays an important role in lipid metabolism as its administration to rats causes a marked depletion of white adipose tissue (WAT). This reduction in fat mass seems to be caused by and related to hipotriglyceridemia as a result of a lower hepatic lipogenesis and an increased fatty acid oxidation. We have previously observed that IL-15 treatment induces the expression of uncoupling proteins (UCPs) in muscle. The aim of this study was to investigate the effects of IL-15 on brown adipose tissue (BAT), and in particular on genes related to lipid metabolism in this tissue.
Male Wistar rats were treated daily with IL-15 for 7 days. Adipose tissues were collected and the mRNA content of UCPs, peroxisome proliferator-activated receptors (PPARs) and several genes implicated in fatty acid transport and oxidation were evaluated on BAT.
IL-15 treatment in rats causes a decrease in the mass of both WAT and BAT (35 and 24%, respectively). In BAT, an important upregulation of the mRNA content of thermogenic proteins (UCP1 and UCP3), lipid-related transcription factors (PPARdelta and PPARalpha) and other proteins implicated in membrane transport (fatty acid translocase (FAT) and fatty acid transport protein (FATP)), mitochondrial transport (carnitine palmitoyl transferase-I (CPT-I) and CPT-II) and consumption (acyl-CoA synthetase 4 (ACS4)) of fatty acids was observed as a consequence of the treatment.
The changes observed in BAT suggest that IL-15 could be implicated in lipid consumption in this tissue by regulating lipid oxidation and probably thermogenesis, processes mediated by UCPs and PPARs.
Obesity 03/2008; 16(2):285-9. · 4.28 Impact Factor
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ABSTRACT: Previous studies have demonstrated an effect of corticotropin-releasing factor 2 receptor (CRF2R) agonists in the maintenance of skeletal muscle mass. The aim of this study was to evaluate the effects of a CRF2R agonist in preserving skeletal muscle in a mouse cachexia model. Implantation of a fast-growing tumor to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. We found that administration of a CRF2R agonist (PG-873637) at 100 microg/kg/day by means of osmotic minipumps to tumor-bearing mice resulted in beneficial effects on muscle weight loss. Thus, muscle loss was partially reversed by the CRF2R agonist at different stages of tumor growth (at day 14 after tumor inoculation: 12% in tibialis posterior; 9% in gastrocnemius; and 48% in soleus). Moreover, the CRF2R agonist significantly reduced both the number of metastases and their mass (at day 19 after tumor inoculation: 66% and 61%, respectively). These data suggest a potentially beneficial effect of the CRF2R agonist in preserving skeletal muscle during cancer cachexia and open a line of research for the development of new therapeutic approaches for the treatment of muscle wasting associated with cancer.
Muscle & Nerve 03/2008; 37(2):190-5. · 2.37 Impact Factor
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ABSTRACT: In rodents and humans, inactivity or starvation leads to atrophy of skeletal muscle including a decrease in the number and size of muscle cells and in the myofibrillar protein content. It has previously been described that in overwintering bears the inactivity does not provoke any loss of skeletal muscle cell number or size. Taking all these into account, the aim of this study is to test if hibernating bear plasma has any antiproteolytic effect on incubated rat skeletal muscle.
Rat skeletal extensor digitorum longus (EDL) muscles were incubated in the presence of hibernating, non-hibernating and control bear plasma. After that, proteolytic rate was evaluated as levels of tyrosine released to the medium and muscle mRNA content for different proteolytic systems were measured by Northern blot.
Rat skeletal EDL muscles incubation in the presence of hibernating bear plasma resulted in a 40% decrease of the net proteolytic rate. This inhibition of proteolysis was accompanied by decreases in the expression of both lysosomal (cathepsin B) and ubiquitin-dependent (ubiquitin) proteolytic systems.
The results suggest that during hibernation the bear is able to produce a powerful proteolytic inhibitor which is released to the circulation and blocks muscle wasting associated with immobilization.
Clinical Nutrition 11/2007; 26(5):658-61. · 3.73 Impact Factor
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ABSTRACT: Implantation of the Yoshida AH-130 ascites hepatoma to rats resulted in a decrease in muscle weight 7 days after the inoculation of the tumor. These changes were associated with increases in the mRNA content for both peroxisome proliferator-activated receptor (PPAR) gamma and PPAR delta in skeletal muscle. The increase in gene expression for these transcription factors was related to increases in the expression of several genes involved in fatty acid transport, activation, and oxidation. Tumor burden also resulted in increases in PPAR gamma coactivator-1 alpha gene expression and pyruvate dehydrogenase kinase 4. All these changes in lipid metabolism genes suggest that a metabolic shift occurs in skeletal muscle of tumor-bearing rats toward a more oxidative phenotype. Formoterol treatment to tumor-bearing rats resulted in an amelioration of all the changes observed as a result of tumor burden. Administration of this beta(2)-adrenergic agonist also resulted in a decrease in mRNA content of muscle PPAR alpha, PPAR delta, and PPAR gamma, as well as in mRNA levels of many of the genes involved in both lipid and mitochondrial metabolism. All these results suggest an involvement of the different PPARs as transcription factors related with muscle wasting and also indicate that a possible mode of action of the anticachectic compound formoterol may involve a normalization of the levels of these transcription factors.
Cancer Research 08/2007; 67(13):6512-9. · 7.86 Impact Factor
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ABSTRACT: Resveratrol has been reported to have antitumoural effects and recently it has been demonstrated that resveratrol partially blocks skeletal muscle wasting by interfering with NF-kappaB activation. We decided to investigate the potential anti-wasting properties of resveratrol on different models of cancer cachexia in experimental animals.
Incubations of isolated extensor digitorum longus muscles in the presence of 30 microM of resveratrol caused a significant decrease in the rate of protein degradation. However, administration of resveratrol in vivo to both rats bearing the Yoshida AH-130 ascites hepatoma (at the dose of 1 mg/kg body weight) and mice bearing the Lewis lung carcinoma (at two different doses, 5 and 25 mg/kg body weight) had no effect on skeletal muscle mass or body weight in tumour-bearing rodents. In addition, a combination of resveratrol (3 mg/kg body weight) and fish oil was also unable to induce any changes in skeletal muscle weights.
It is therefore concluded from this study that resveratrol is unable to influence muscle mass in vivo and has no potential role as anticachectic agent for the treatment of muscle wasting associated with tumour growth.
Clinical Nutrition 04/2007; 26(2):239-44. · 3.73 Impact Factor
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ABSTRACT: Administration of different doses of the diphenol resveratrol had no effect on the growth of an intramuscularly implanted experimental tumour, the Lewis lung carcinoma. These results do not agree with previous reports where a clear effect of resveratrol was shown on tumour burden in both mice and rats. However, administration of the diphenol had a clear anti-metastatic effect, decreasing both the number and the weight of the lung metastases. Similar effects were observed both at 5 and 25mg/kg body weight per day, resulting in an approximately 40% reduction in the number of metastases. These results suggest that resveratrol could be tentatively given as a preventive agent in cancer patients undergoing radiotherapy or chemotherapy.
Cancer Letters 02/2007; 245(1-2):144-8. · 4.24 Impact Factor
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ABSTRACT: Interleukin 15 (IL-15) has previously been shown to have important effects on lipid metabolism in adipose tissue, particularly influencing the rate of the de novo fatty acid synthesis. The results presented here show that chronic administration to rats (100 microg/kg body weight) has important effects on the metabolic fate of an exogenous [(14)C]-triolein load, decreasing the incorporation of lipid into adipose tissue and significantly increasing the total (14)CO(2) formation from [(14)C]-triolein. Skeletal muscle and possibly liver seem to be the main organs involved in the action of IL-15 on lipid oxidation, since the presence of the cytokine in incubated EDL muscle with [(14)C]-palmitic acid increased (14)CO(2) formation by 39%. Concerning the mechanism, the results suggest that the transport of fatty acids into mitochondria could be involved in the action of IL-15 since the cytokine clearly increases the presence of L-CPT-I and CPT-II in liver tissue. In addition, IL-15 treatment resulted in a significant increment in the gene expression of PPARdelta, a transcription factor clearly related with lipid catabolism in many tissues. Altogether, the results presented here suggest that IL-15 alters exogenous lipid partitioning, limiting adipose tissue uptake and favouring oxidation.
Biochimica et Biophysica Acta 02/2006; 1761(1):37-42. · 4.66 Impact Factor
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ABSTRACT: In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the beta2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the beta2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.
Cancer Research 10/2004; 64(18):6725-31. · 7.86 Impact Factor
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ABSTRACT: Voltage-dependent K+ channels (VDPC) are expressed in most mammalian cells and involved in the proliferation and activation of lymphocytes. However, the role of VDPC in macrophage responses is not well established. This study was undertaken to characterize VDPC in macrophages and determine their physiological role during proliferation and activation. Macrophages proliferate until an endotoxic shock halts cell growth and they become activated. By inducing a schedule that is similar to the physiological pattern, we have identified the VDPC in non-transformed bone marrow-derived macrophages and studied their regulation. Patch clamp studies demonstrated that cells expressed outward delayed and inwardly rectifying K+ currents. Pharmacological data, mRNA, and protein analysis suggest that these currents were mainly mediated by Kv1.3 and Kir2.1 channels. Macrophage colony-stimulating factor-dependent proliferation induced both channels. Lipopolysaccharide (LPS)-induced activation differentially regulated VDPC expression. While Kv1.3 was further induced, Kir2.1 was down-regulated. TNF-alpha mimicked LPS effects, and studies with TNF-alpha receptor I/II double knockout mice demonstrated that LPS regulation mediates such expression by TNF-alpha-dependent and -independent mechanisms. This modulation was dependent on mRNA and protein synthesis. In addition, bone marrow-derived macrophages expressed Kv1.5 mRNA with no apparent regulation. VDPC activities seem to play a critical role during proliferation and activation because not only cell growth, but also inducible nitric-oxide synthase expression were inhibited by blocking their activities. Taken together, our results demonstrate that the differential regulation of VDPC is crucial in intracellular signals determining the specific macrophage response.
Journal of Biological Chemistry 12/2003; 278(47):46307-20. · 4.77 Impact Factor
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ABSTRACT: Cancer cachexia is a syndrome characterised by a marked weight loss, anorexia, asthenia and anaemia. In fact, many patients who die with advanced cancer suffer from cancer cachexia. The cachectic state is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated starvation state which promotes severe metabolic disturbances in the host, including hypermetabolism which leads to an increased energetic inefficiency. Although, the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from knowing the whole truth. The main aim of the present review is to summarise and evaluate the different catabolic mediators (both humoural and tumoural) involved in cancer cachexia since they may represent targets for future promising clinical investigations.
The International Journal of Biochemistry & Cell Biology 05/2003; 35(4):405-9. · 4.63 Impact Factor
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ABSTRACT: Interleukin 15 (IL-15) has previously been shown to have important effects on lipid metabolism in adipose tissue, particularly influencing the rate of the de novo fatty acid synthesis. The results presented here show that chronic administration to rats (100 μg/kg body weight) has important effects on the metabolic fate of an exogenous [14C]-triolein load, decreasing the incorporation of lipid into adipose tissue and significantly increasing the total 14CO2 formation from [14C]-triolein. Skeletal muscle and possibly liver seem to be the main organs involved in the action of IL-15 on lipid oxidation, since the presence of the cytokine in incubated EDL muscle with [14C]-palmitic acid increased 14CO2 formation by 39%. Concerning the mechanism, the results suggest that the transport of fatty acids into mitochondria could be involved in the action of IL-15 since the cytokine clearly increases the presence of L-CPT-I and CPT-II in liver tissue. In addition, IL-15 treatment resulted in a significant increment in the gene expression of PPARδ, a transcription factor clearly related with lipid catabolism in many tissues. Altogether, the results presented here suggest that IL-15 alters exogenous lipid partitioning, limiting adipose tissue uptake and favouring oxidation.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.
