Zbinden Foncea, Hermann
[UCL]
(eng)
Toll-like receptors 2 (TLR2) and 4 (TLR4) are present in the plasma membrane of skeletal muscles, where their functions are only partially understood. A variety of molecular components could activate TLR2 and TLR4, including non-esterified fatty acids (NEFA). NEFA are also known to be released during endurance exercise. Likewise, endurance exercise may activate known downstream targets of TLR2 and TLR4 such as mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB).
The purpose of this work was to investigate the possible interaction between the elevated plasma NEFA observed during endurance exercise and the MAPK activation mediated by TLR2 and TLR4. From a methodological point of view, three experimental models were used: myotubes cultured from C2C12 cells, soleus and tibialis muscle from C57BL/6J animals wild-type (WT) and transgenic tlr2-/- and tlr4-/- mice, and finally, muscle biopsies taken from the vastus lateralis of healthy and diabetic subjects.
Palmitic acid (PA) was able to increase p38 MAPK and S6K1 phosphorylation accompanied by PKB inhibition in C2C12. TLR2 and TLR4 seem to be implicated in this phenomenon. In addition, our results showed evidence of a possible crosstalk between S6K1 and p38 MAPK, induced by PA elevation. When mice were submitted to an endurance exercise, plasma NEFA levels increased. Likewise, we observed an increase of p38 MAPK, JNK and c-Jun phosphorylation in the muscles of WT mice. These effects were not observed in tlr2-/- and tlr4-/- mice, which suggests that TLR2 and TLR4 are necessary to activate the above-mentioned proteins. Acipimox was used prior to and during endurance exercise to prevent the elevation of plasma NEFA levels in healthy and diabetic subjects. Our findings have shown an increase in the phosphorylation levels of ERK1/2, p38 MAPK and JNK after exercise in both groups. Acipimox was able to suppress the increase of plasma NEFA, resulting in a concomitant repression of p38 MAPK and ERK1/2 but not in the JNK phosphorylation induced by endurance exercise. On the other hand, the NF-κB pathways were unaffected by our endurance protocols in both mouse and human models.
Our data support a role for plasma FA in the activation of MAPK during endurance exercise. This activation may be mediated by TLR2 and TLR4 in skeletal muscle
Bibliographic reference |
Zbinden Foncea, Hermann. Activation of Toll Like receptors 2 and 4 by fatty acids in skeletal muscle. Prom. : Francaux, Marc ; Raymackers, jean-Marc |
Permanent URL |
http://hdl.handle.net/2078.1/128993 |