After nerve injury, the protein complex mTORC1 takes over an important function in skeletal muscle to maintain the neuromuscular junction, the synapse between the nerve and muscle fiber. Researchers have now shown that the activation of mTORC1 must be tightly balanced for a proper response of the muscle to nerve injury. The study published in Nature Communications opens new insights into muscle weakness related to neuromuscular diseases or caused by ageing.
Nerves and muscles in our body are connected by specialized synapses, called neuromuscular junctions, which transmit signals from the nerve to muscle fibers. If innervation is lost or interrupted by the injury of the nerve, muscles cannot contract anymore. However, to prepare the muscle for re-innervation by the nerve, the muscle component of the neuromuscular junction, the motor endplate, is maintained. The research team has now more closely studied the function of mTORC1 and its upstream kinase PKB/Akt in the maintenance of the motor endplate after nerve injury using different mouse models.
The best known function of the PKB/Akt - mTORC1 signaling pathway is to promote muscle growth and the cellular self-cleaning process. “We have now been able to show that PKB/Akt and mTORC1 also play an important role in the maintenance of the neuromuscular endplate”, explains first author of the study.
After nerve damage, both PKB/Akt and mTORC1 get activated in muscle fibers. The study demonstrates that mTORC1 should not be activated too strongly nor too little to ensure a proper response of the muscle. Acutely activating or inhibiting mTORC1 impairs autophagy regulation and alters homeostasis in denervated muscle. Importantly, PKB/Akt inhibition, conferred by sustained mTORC1 activation, abrogates denervation-induced synaptic remodeling and causes neuromuscular endplate degeneration: “Should mTORC1 be too strongly activated, PKB/Akt is inhibited, resulting in the loss of the neuromuscular endplate. Balanced activation of both PKB/Akt and mTORC1 is required for the proper response of the muscle fiber”, says the author.
The authors establish that PKB/Akt activation promotes the nuclear import of HDAC4 and is thereby required for epigenetic changes and synaptic gene up-regulation upon denervation. The newly described function of PKB/Akt and mTORC1 opens new perspective on how age-related muscle atrophy develops in humans. This is, likewise, induced through an alteration of neuromuscular endplates and possibly by over-activation of mTORC1.
“Through this study, we now better understand the molecular mechanisms contributing to the maintenance of the neuromuscular junctions. Based on our results, we may be able to develop new approaches to potentially counteract age-related deficits and structural changes in order to better preserve the performance and functional capabilities of the muscles during ageing”, says the senior author.
https://www.unibas.ch/en/News-Events/News/Uni-Research/How-neuromuscular-connections-are-maintained-after-nerve-lesions.html
https://www.nature.com/articles/s41467-019-11227-4
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fmtorc1-and-pkb-akt&filter=22&redirected=1
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