AMPK activation regulates P-body dynamics in mouse sensory neurons in vitro and in vivo

Abstract Increased mRNA translation in sensory neurons following peripheral nerve injury contributes to the induction and maintenance of chronic neuropathic pain. Metformin, a common anti-diabetic drug and an activator of AMP-activated protein kinase (AMPK), inhibits cap-dependent mRNA translation and reverses mechanical hypersensitivity caused by a neuropathic injury in both mice and rats. P-bodies are RNA granules that comprise sites for metabolizing mRNA through the process of de-capping followed by RNA decay. These RNA granules may also sequester mRNAs for storage. We have previously demonstrated that induction of cap-dependent translation in cultured trigeminal ganglion (TG) neurons decreases P-body formation and AMPK activators increase P-body formation. Here we examined the impact of AMPK activation on protein synthesis and P-body formation in vitro and in vivo on mouse dorsal root ganglion (DRG) neurons. We demonstrate that AMPK activators inhibit nascent protein synthesis and increase P-body formation in DRG neurons. We also demonstrate that mice with a spared-nerve injury (SNI) show decreased P-bodies in the DRG, consistent with increased mRNA translation resulting from injury. Metformin treatment normalizes this effect in SNI mice and increases P-body formation in sham animals. These findings indicate that P-bodies are dynamically regulated by nerve injury in vivo and this effect can be regulated via AMPK activation.