Speaker: Rafael Salto, PhD
Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada – Spain

HOST

 Dr. Joan Guinovart, IRB Barcelona

Wednesday, 21 July 2010, 13:00h, Aula Fèlix Serratosa

ABSTRACT

Sodium tungstate is a well characterized anti-diabetic compound able to normalize hepatic glucose metabolism. Furthermore, tungstate has interesting antiobesity properties. We have focused our efforts in the characterization of sodium tungstate effects on skeletal muscle. In rat animal models and cell cultures of L6 myotubes, sodium tungstate is able to increase the amount of GLUT4 transporter as well as promote its translocation to the plasma membrane. Both effects produce an increased peripheral glucose uptake and justify part of its anti-diabetic properties. We have also found than sodium tungstate exercises pleiotropic effects in skeletal muscle cells: tungstate is able to increase myoblast differentiation to myotubes that translates in an increase in the number of multinucleate cells, higher creatine kinase promoter and enzyme activities and, may be more interesting, produces an increase in net protein synthesis. All these effects are independent of Akt/PKB, AMPK and p38MAK signaling pathways. On the contrary, are fully dependent of ERK1/2 signaling. Experiments using deletions of the creatine kinase promoter point out to the MEF2 (myocyte enhancer factor 2) family of transcriptional regulators are responsible of the tungstate effects in muscle. Tungstate is able to post-transductionally increase the amount of members of the MEF2D family, mainly MEF2D. MEF2 members have a complex regulation of their activity including alternative splicing, phosphorylation and sumoylation. The main protein kinase responsible of the regulation of MEF2D is PKA. We have studied the relationship between cAMP and tungstate modulation of MEF2D activity using site directed mutagenesis (positions T20, S121 and S190 phosphorylated by PKA and additionally position K439, the sumoylation residue). Tungstate effects on the MEF2D mediated transcriptional activity are completely blocked by mutation of serine 121. These results are also supported by the fact that the increase in PKA activity, due to addition of Br-cAMP, forskolin or over-expression on PKA catalytic subunits, also inhibits tungstate effects. All together, these results reveal the relevance of the serine in position 121 in the regulation by sodium tungstate of the MEF2 family. In conclusion, the positive effects of tungstate in protein synthesis and differentiation in muscle, could point out to tungstate as a lead compound for the restoration of lean body mass in several pathologies.
Work funded by Marcelino Botín Foundation.
 

• Download Poster