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TLR2 and TLR4 activate p38 MAPK and JNK during endurance exercise in skeletal muscle

机译：骨骼肌耐力运动过程中TLR2和TLR4激活p38 MAPK和JNK

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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-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. 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 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. 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.
机译：目的：在骨骼肌细胞膜中发现Toll样受体2和4（TLR2，TLR4）。各种分子成分可以激活TLR2和TLR4，尤其是长链脂肪酸。随后的下游信号触发有丝分裂原激活的蛋白激酶（MAPK）和核因子-κB（NF-κB）通路。因此，本研究的目的是测试耐力运动期间观察到的细胞外非酯化脂肪酸（NEFA）的升高是否可以通过TLR2和TLR4激活MAPK和NF-κB途径。方法：将tlr2和tlr4小鼠以及野生型C57BL / 6J动物（WT）进行标准化耐力锻炼。结果：运动后，WT胫骨前肌（TA）和比目鱼肌（SOL）的p38 MAPK，c-Jun NH2-末端激酶（JNK）和c-Jun的磷酸化状态升高（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。 p38 MAPK，JNK和c-Jun的激活在tlr2-/-和tlr4-/-小鼠的TA中完全减弱，而在SOL中，它仅占WT小鼠中观察到的增加的25％。通过向小鼠注射肝素来评估NEFA浓度与MAPK活化之间的因果关系。肝素注射后观察到的血浆NEFA升高与耐力运动后相似。 JNK和p38 MAPK在WT的TA和SOL中被肝素激活（P <0.05），但在tlr2-/-和tlr4-/-小鼠的肌肉中未激活。结论：本研究支持这样的想法，即在耐力运动期间，TLR2和TLR4介导信号，将血浆NEFA浓度升高与p38 MAPK和JNK的激活联系起来。

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