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Published on: July 26, 2017
TLR2 and TLR4 activate p38 MAPK and JNK during endurance exercise in skeletal muscle
Hermann Zbinden-Foncea1, Jean-Marc Raymackers, Louise Deldicque
1Institute of Neuroscience, Medical Sector, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
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.
Insights
Endurance exercise activates specific cell signaling pathways in muscles via Toll-like receptors 2 and 4 (TLR2, TLR4). These receptors link elevated fatty acids to the activation of p38 MAPK and JNK signaling.
Area of Science:
- Skeletal muscle physiology
- Immunology
- Molecular biology
Background:
- Toll-like receptors 2 and 4 (TLR2, TLR4) are present in skeletal muscle cell membranes.
- Long-chain fatty acids can activate TLR2 and TLR4, initiating downstream signaling via MAPK and NF-κB pathways.
Purpose of the Study:
- To investigate if elevated extracellular nonesterified fatty acids (NEFA) during endurance exercise activate MAPK and NF-κB pathways through TLR2 and TLR4.
Main Methods:
- Endurance exercise was performed on wild-type (WT) and tlr2/tlr4 knockout mice.
- Muscle signaling pathway activation (MAPK, NF-κB) was assessed post-exercise.
- The effect of heparin injection on NEFA levels and MAPK activation was examined.
Main Results:
- Exercise increased p38 MAPK, JNK, and c-Jun phosphorylation in WT mice, but not ERK1/2 or NF-κB.
- This activation was significantly reduced in tlr2/tlr4 mice.
- Heparin-induced NEFA increase mimicked exercise effects on MAPK activation in WT mice, but not in tlr2/tlr4 mice.
Conclusions:
- Endurance exercise-induced activation of p38 MAPK and JNK in skeletal muscle is mediated by TLR2 and TLR4.
- These receptors act as a link between increased plasma NEFA and muscle cell signaling pathways.
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