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

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.

Formoterol and cancer muscle wasting in rats: Effects on muscle force and total physical activity

“…This effect was observed in the gastrocnemius, tibialis and extensor digitorum longus (EDL) muscles and also in the heart. Similar results were previously described by our research group (19,23). Indeed, formoterol and other β 2 -agonists such as clenbuterol were found to be effective in ameliorating muscle weight loss during wasting (19,23,24).…”

“…Similar results were previously described by our research group (19,23). Indeed, formoterol and other β 2 -agonists such as clenbuterol were found to be effective in ameliorating muscle weight loss during wasting (19,23,24). At the biochemical level, the mechanisms underlying the effects of the β 2 -agonist are complex.…”

Novel investigational drugs mimicking exercise for the treatment of cachexia

“…Treatment of L6 myotubes with the GW0742 increases protein degradation and reduces myotube size, and rats administered the PPARδ inhibitor GSK0660 are resistant to glucocorticoid or sepsis-induced muscle protein breakdown (58) . These findings are in line with previous data showing that PPARδ expression is induced in the skeletal muscle of tumor-bearing rats (59) . A final consideration is that glitazones show several severe side effects, including cardiovascular and hepatic adverse events and increased risk of cancer development (60) .…”

PPARδ mediates IL15 metabolic actions in myotubes: Effects of hyperthermia

“…Analysis of mRNA levels for PPAR‰ was performed with primers designed to detect gene products as previously described (24). To avoid the detection of possible contamination by genomic DNA, primers were designed to be located on different exons.…”