Institute of Neuroscience, Medical Sector, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
Med Sci Sports Exerc. 2012 Aug;44(8):1463-72. doi: 10.1249/MSS.0b013e31824e0d5d.
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-κB (NF-κB) 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-κB pathways via TLR2 and TLR4.
tlr2 and tlr4 mice and wild-type C57BL/6J animals (WT) were submitted to a standardized endurance exercise.
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 IκB kinase α/β and the DNA-binding of NF-κB 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.
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.
Toll 样受体 2 和 4（TLR2、TLR4）存在于骨骼肌细胞膜中。许多分子成分可以激活 TLR2 和 TLR4，其中包括长链脂肪酸。随后的下游信号触发丝裂原活化蛋白激酶（MAPK）和核因子-κB（NF-κB）途径。因此，本研究旨在测试在耐力运动期间观察到的细胞外非酯化脂肪酸（NEFA）升高是否可以通过 TLR2 和 TLR4 激活 MAPK 和 NF-κB 途径。
tlr2 和 tlr4 小鼠和野生型 C57BL/6J 动物（WT）进行了标准化的耐力运动。
运动后即刻，WT 动物的比目鱼肌（TA）和跖肌（SOL）中 p38 MAPK、c-Jun NH2-末端激酶（JNK）和 c-Jun 的磷酸化状态增加（P < 0.05）。细胞外信号调节激酶 1 和 2（ERK1/2）和 IκB 激酶α/β的磷酸化状态以及 NF-κB 的 DNA 结合保持不变。TLR2 和 TLR4 小鼠的 TA 中 p38 MAPK、JNK 和 c-Jun 的激活完全被阻断，而在 SOL 中，其仅代表 WT 小鼠观察到的增加的 25%。通过向小鼠注射肝素来评估 NEFA 浓度与 MAPK 激活之间的因果关系。肝素注射后观察到血浆 NEFA 浓度类似增加。WT 动物的 TA 和 SOL 中肝素诱导 JNK 和 p38 MAPK 激活（P < 0.05），但 TLR2 和 TLR4 小鼠的肌肉中没有激活。
本研究支持这样一种观点，即在耐力运动期间，TLR2 和 TLR4 介导将升高的血浆 NEFA 浓度与 p38 MAPK 和 JNK 的激活相关联的信号。
