TLR2 and TLR4 Activate p38 MAPK and JNK during Endurance Exercise in Skeletal Muscle

ZBINDEN-FONCEA, H., J.-M. RAYMACKERS, L. DELDICQUE, P. RENARD, and M. FRANCAUX. TLR2 and TLR4 Activate p38 MAPK and JNK during Endurance Exercise in Skeletal Muscle. Med. Sci. Sports Exerc., Vol. 44, No. 8, pp. 1463-1472, 2012. Purpose: Toll-like receptors 2 and 4 (TLR2, TLR4) are found in the membrane of skeletal muscle cells. A variety of molecular components can activate TLR2 and TLR4, among others, long-chain fatty acids. The subsequent downstream signaling triggers the mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-kappa B) pathways. Therefore, the purpose of this study was to test whether an elevation of extracellular nonesterified fatty acids (NEFA) observed during endurance exercise may activate the MAPK and NF-kappa B pathways via TLR2 and TLR4. Methods: tlr2(-/-) and tlr4(-/-) mice and wild-type C57BL/6J animals (WT) were submitted to a standardized endurance exercise. Results: Immediately after exercise, the phosphorylation state of p38 MAPK, c-Jun NH2-terminal kinase (JNK), and c-Jun was increased in the tibialis anterior (TA) and soleus (SOL) muscles of WT (P < 0.05). The phosphorylation state of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and I kappa B kinase alpha/beta and the DNA-binding of NF-kappa B remained unchanged. The activation of p38 MAPK, JNK, and c-Jun was completely blunted in TA of tlr2(-/-) and tlr4(-/-) mice, whereas in SOL, it represented only 25% of the increase observed in WT mice. The causal relationship between NEFA concentration and MAPK activation was evaluated by injecting mice with heparin. A similar increase in plasma NEFA was observed after heparin injection than after endurance exercise. JNK and p38 MAPK were activated under heparin in TA and SOL of WT (P < 0.05) but not in muscles of tlr2(-/-) and tlr4(-/-) mice. Conclusions: The present study supports the idea that during endurance exercise, TLR2 and TLR4 mediate a signal linking the elevated plasma NEFA concentration to the activation of p38 MAPK and JNK.