Are Peroxisome Proliferator-Activated Receptors Involved in Skeletal Muscle Wasting during Experimental Cancer Cachexia? Role of B 2 -Adrenergic Agonists Gemma Fuster, Sı ´lvia Busquets, Elisabet Ametller, Mireia Olivan, Vanessa Almendro, Cibely Cristine Fontes de Oliveira, Maite Figueras, Francisco J. Lo ´pez-Soriano, and Josep M. Argile ´s Cancer Research Group, Departament de Bioquı ´mica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain 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 prolifer- ator-activatedreceptor(PPAR) ; andPPARD inskeletalmuscle. 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. TumorburdenalsoresultedinincreasesinPPAR; coactivator- 1A gene expression and pyruvate dehydrogenase kinase 4. All these changes in lipid metabolism genes suggest that a metabolicshiftoccursinskeletalmuscleoftumor-bearingrats 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 B 2 -adrenergic agonist also resulted in a decrease in mRNAcontentofmusclePPARA,PPARD,andPPAR;,aswellas inmRNAlevelsofmanyofthegenesinvolvedinbothlipidand 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 modeofactionoftheanticachecticcompoundformoterolmay involve a normalization of the levels of these transcription factors. [Cancer Res 2007;67(13):6512–9] Introduction Muscle wasting is a common feature in many pathologic states, including infection and cancer (1). Muscle wasting, the main trend of cachexia, is responsible for the death of at least 30% of cancer patients (2). Although we know the main events related with muscle wasting [activation of myofibrillar protein degradation, induction of apoptosis, and activation of uncoupling proteins (UCP); refs. 3, 4], we have contradictory evidence about the possible mediators involved. Indeed, whereas involvement of different cytokines, mainly tumor necrosis factor-a (TNFa) and interleu- kin-6 (IL-6), has been postulated, other studies describe a more direct role for tumor-derived factors, such as proteolysis-inducing factor (PIF) and lipid-mobilizing factor (5, 6). The intracellular signaling pathway may have a key role, from a therapeutic point of view, especially if there are different mediators involved. Taking this into consideration, a lack of knowledge about signaling pathways and transcription factors involved in muscle wasting exists. Some work has postulated a role for nuclear factor-nB (NF-nB) in muscle wasting associated with cytokines (7) and tumor-derived factors (8). Other transcription factors, such as activator protein-1 (AP-1) and CCAAT/enhancer binding protein (C/EBP), have also been involved in sepsis-induced muscle cachexia (9). Results from our laboratory indicate that the transcription factor AP-1 could also be involved during cancer cachexia (10, 11). Not much attention has been focused on the role of peroxisome proliferator-activated receptors (PPAR) in skeletal muscle. These transcription factors are associated with changes in lipid metabolism as well as UCP expression (12) and apoptosis (13). PPARs are transcription factors belonging to the superfamily of nuclear receptors. Three isoforms (a, y, and g) have been described (14). They act on DNA response elements as heterodimers with the nuclear retinoic acid receptor. Their natural activating ligands are fatty acids and lipid-derived substrates. PPARa is present in liver, heart, and, to a lesser extent, skeletal muscle; when activated, it promotes fatty acid oxidation, ketone body synthesis, and glucose sparing. PPARg is expressed in adipose tissue, lower intestine, skeletal muscle, and immune cells; activation of PPARg induces the differentiation of preadipocytes into adipocytes and stimulates triglyceride storage. The PPARs are thus major regulators of lipid and glucose metabolism, allowing adaptation to the prevailing nutritional environment (14). PPARy has a broad expression pattern in adult and is expressed very early during embryogenesis (15). These past few years, it has been shown that treatment with PPARy agonists normalizes blood lipids and also reduces insulin resistance and adiposity in rodents and primates. Utilization of both cellular and animal models revealed that this nuclear receptor plays a central role in the control of fatty acid burning in adipose tissue and skeletal muscle. Furthermore, PPARy seemed to be important for adaptive response of skeletal muscle to environ- mental changes, such as physical exercise (15). h 2 -adrenergic agonists are potent muscle growth promoters in many animal species (16, 17), resulting in skeletal muscle hypertrophy (18–20) and reducing body fat content (21, 22). Interestingly, results from our laboratory clearly indicate that formoterol is a very efficient agent preventing muscle weight loss in tumor-bearing rats (23). In vivo treatment can effectively reverse muscle wasting loss decreasing protein degradation and increasing the rate of protein synthesis in skeletal muscle, therefore favoring protein accretion (23). Bearing this in mind, the aim of the present investigation was to ascertain if tumor burden induces any changes in PPARs gene transcription in skeletal muscle and if these changes are associated Requests for reprints: Josep M. Argile ´s, Cancer Research Group, Departament de Bioquı ´mica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08028 Barcelona, Spain. Phone: 34-934021002; Fax: 34-934021559; E-mail: jargiles@ub.edu. I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-0231 Cancer Res 2007; 67: (13). July 1, 2007 6512 www.aacrjournals.org Research Article Research. on January 10, 2022. © 2007 American Association for Cancer cancerres.aacrjournals.org Downloaded from