Maite Figueras

Interleukin‐15 is able to suppress the increased DNA fragmentation associated with muscle wasting in tumour‐bearing rats

Administration of interleukin‐15 (IL‐15) to rats bearing the Yoshida AH‐130 ascites hepatoma (a tumour that induces an important cachectic response) resulted in a significant reduction of muscle wasting, both measured as muscle weight and as protein content of different types of skeletal muscle. In addition, the administration of the cytokine completely reversed the increased DNA fragmentation observed in skeletal muscle of tumour‐bearing animals. Concerning the mechanism(s) involved in the anti‐apoptotic effects of IL‐15 on skeletal muscle, the administration of the cytokine resulted in a considerable decrease in both R1 (43%) and R2 (64%) TNF‐α receptors (TNFRs), and therefore it may be suggested that IL‐15 decreases apoptosis by affecting TNF‐α signalling. Formation of NO could be the signalling event associated with the activation of apoptosis in muscle of tumour‐bearing rats; indeed, administration of IL‐15 decreased the inducible nitric oxide synthase protein levels by 73%, suggesting that NO formation and muscle apoptosis during tumour growth are related. In conclusion, IL‐15 seems to be able to reduce/suppress protein loss and apoptosis related to muscle wasting during cancer cachexia in experimental animals.

Effects of Eicosapentaenoic Acid (EPA) Treatment on Insulin Sensitivity in an Animal Model of Diabetes: Improvement of the Inflammatory Status

In addition to decreased insulin sensitivity, diabetes is a pathological condition associated with increased inflammation. The ω‐3 fatty acids have been proposed as anti‐inflammatory agents. Thus, the major goal of this study was to analyze the effects of fatty acid supplementation on both insulin sensitivity and inflammatory status in an animal model of type 2 diabetes. Diabetic rats (Goto‐Kakizaki model) were treated with eicosapentaenoic acid (EPA) or linoleic acid at 0.5 g/kg body weigh (bw) dose. In vivo incorporation of 14C‐triolein into adipose tissue was improved by the ω‐3 administration. In vitro incubations of adipose tissue slices from EPA‐treated rats showed an increase in 14C‐palmitate incorporation into the lipid fraction. These observations were linked with a decreased rate of fatty acid oxidation. EPA treatment resulted in a decreased fatty acid oxidation in incubated strips from extensor digitorum longus (EDL) muscles. The changes in lipid utilization were associated with a decrease in insulin plasma concentration, suggesting an improvement in insulin sensitivity. These changes in lipid metabolism were associated with an activation of AMP‐activated protein kinase (AMPK) in white adipose tissue. In addition, EPA treatment resulted in a decreased content of peroxisome proliferator‐activated receptor‐α (PPARα) and PPARδ and in increased GLUT4 expression in skeletal muscle. Moreover, EPA increased 2‐deoxy‐D‐[14C]glucose (2‐DOG) uptake in C2C12 myotubes, suggesting an improvement in glucose metabolism. Concerning the inflammatory status, EPA treatment resulted in a decreased gene expression for both tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) both in skeletal muscle and adipose tissue. The data suggest that EPA treatment to diabetic rats clearly improves lipid metabolism although the evidences on insulin sensitization are less clear.

Activation of UCPs gene expression in skeletal muscle can be independent on both circulating fatty acids and food intake: Involvement of ROS in a model of mouse cancer cachexia

Implantation of a fast growing tumour to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. This was accompanied by a significant increase in both UCP2 and UCP3 gene expression in skeletal muscle and heart. Interestingly, this increase in gene expression was not linked to a rise in circulating fatty acids or in a decrease in food intake, as previously reported in other pathophysiological states. These results question the concept that hyperlipaemia is the only factor controlling UCP gene expression in different pathophysiological conditions. In addition, the present work suggests that UCPs might participate in a counter‐regulatory mechanism to lower the production of ROS.

Are Peroxisome Proliferator-Activated Receptors Involved in Skeletal Muscle Wasting during Experimental Cancer Cachexia? Role of β2-Adrenergic Agonists

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.

Hyperlipemia: a role in regulating UCP3 gene expression in skeletal muscle during cancer cachexia?

Rats bearing the Yoshida AH‐130 ascites hepatoma showed an increased expression of both uncoupling protein‐2 (UCP2) (two‐fold) and UCP3 (three‐ to four‐fold) in skeletal muscle (both soleus and gastrocnemius). The increase in mRNA content was associated with increased circulating concentrations of fatty acids (two‐fold), triglyceride (two‐fold) and cholesterol (1.9‐fold). Administration of nicotinic acid to tumor‐bearing rats abolishes the hyperlipidemic increase associated with tumor burden. The vitamin treatment also resulted in a decreased UCP3 gene expression in soleus muscle but not in gastrocnemius. It is concluded that circulating fatty acids may be involved in the regulation of UCP3 gene expression in aerobic muscles during experimental cancer cachexia. Since the UCP3 protein could have a role in energy expenditure, it may be suggested that hypolipidemic agents may have a beneficial role in the treatment of the cachectic syndrome.

Effects of IL-15 on Rat Brown Adipose Tissue : Uncoupling Proteins and PPARs

Objectives: 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.

Effects of CRF2R agonist on tumor growth and cachexia in mice implanted with Lewis lung carcinoma cells.

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 μg/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, 2007

Theophylline is able to partially revert cachexia in tumour-bearing rats

Background and aimsThe aim of the present investigation was to examine the anti-wasting effects of theophylline (a methylxantine present in tea leaves) on a rat model of cancer cachexia.MethodsThe in vitro effects of the nutraceuticals on proteolysis were examined on muscle cell cultures submitted to hyperthermia. Individual muscle weights, muscle gene expression, body composition and cardiac function were measured in rats bearing the Yoshida AH-130 ascites hepatoma, following theophylline treatment.ResultsTheophylline treatment inhibited proteolysis in C2C12 cell line and resulted in an anti-proteolytic effect on muscle tissue (soleus and heart), which was associated with a decrease in circulating TNF-alpha levels and with a decreased proteolytic systems gene expression. Treatment with the nutraceutical also resulted in an improvement in body composition and cardiac function.ConclusionTheophylline - alone or in combination with drugs - may be a candidate molecule for the treatment of cancer cachexia.

Nutraceutical inhibition of muscle proteolysis : a role of diallyl sulphide in the treatment of muscle wasting

BACKGROUND & AIMS The abnormalities associated with cancer cachexia include anorexia, weight loss, muscle loss and atrophy, anaemia and alterations in carbohydrate, lipid and protein metabolism. The aim of the present investigation was to examine the anti-wasting effects of some nutraceuticals such as genistein, resveratrol, epigallocatechin gallate and diallyl sulphide (DAS). METHODS The in vitro effects of these nutraceuticals on proteolysis were examined in muscle cell cultures submitted to hyperthermia. The in vivo effects of DAS were also tested in cachectic tumour-bearing rats (Yoshida AH-130 ascites hepatoma). RESULTS Although all the nutraceuticals tested inhibited muscle proteolysis, the most promising effects were related with DAS. In vivo administration of DAS only leads to a small improvement in tibialis muscle and heart weights; however, administration of DAS to healthy animals increased all muscle weights, this being associated with a decreased gene expression of proteolytic systems components. CONCLUSION It may be suggested that DAS could be used to improve muscle mass during healthy conditions.

A differential pattern of gene expression in skeletal muscle of tumor‐bearing rats reveals dysregulation of excitation–contraction coupling together with additional muscle alterations

Introduction: Cachexia is a wasting condition that manifests in several types of cancer. The main characteristic of this condition is a profound loss of muscle mass. Methods: By using a microarray system, expression of several hundred genes was screened in skeletal muscle of rats bearing a cachexia‐inducing tumor, the AH‐130 Yoshida 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 with cachexia and control animals. Conclusions: The differences observed pertain to 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. Assessment of these differences may be a useful tool for the design of novel therapeutic strategies to fight this devastating syndrome. Muscle Nerve 49: 233–248, 2014