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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.

(C)2012The American College of Sports Medicine