THE IMPACT OF ADENOSINE A2B RECEPTORS ON GLYCOLYSIS AND INSULIN RESISTANCE IN SKELETAL MUSCLE

Adenosine has been proposed as a key factor regulating the metabolic balance between energy supply and demand in skeletal muscle. Adenosine A2B receptors are expressed across multiple tissues including skeletal muscle. Previously, it has been identified the robust (in vitro) induction of the nuclear receptors (NR4A) subgroup following adenosine A2B receptors stimulation in rat skeletal muscle cells. This may be concomitant with changes in the expression of genes involved in the regulation of nutrient metabolism. Considering that skeletal muscle is a primary tissue responsible for glucose disposal, glucose oxidation and insulin resistance, this study investigated a potential functional role for adenosine A2B receptors in rat L6 skeletal muscle myotubes in terms of glycolysis (HKII and PFK), and insulin resistance/glucose oxidation (PDK4) using a transcriptional approach (QRT-PCR (Probe-based)). For the first time in rat skeletal muscle cells, the results of the present study have shown that stable adenosine analogue NECA alters the expression of a number of genes (HKII, and PFK). Moreover, this is the first study demonstrating that selective adenosine A2B receptors antagonist/inverse agonist PSB 603 alters the expression of a number of genes (HKII, PFK, and PDK4). To our knowledge, this is the first study also demonstrating an alteration of PFK gene by selective adenosine A2A receptors agonist CGS 21680. Adenosine A2B receptors mediate both NECA (adenosine-5’N-ethylcarboxamide)-induced HKII, and NECA-inhibited PFK mRNA gene expression in skeletal muscle cells. These results indicate that adenosine A2B receptors play a critical role in the regulation of metabolic function in skeletal muscle. Collectively, these data reveal adenosine A2B receptors as a novel target to consider in our understanding of metabolic function and risk for the development of metabolic-based diseases.