The miR-206-3p/Cpeb1 axis delays acetylcholine receptor degradation and preserves neuromuscular junction stability in denervation-induced muscle atrophy.

Abstract

Peripheral nerve injury leads to progressive neuromuscular junction (NMJ) destabilization and acetylcholine receptor (AChR) degradation, which are critical drivers of denervation-induced muscle atrophy and impaired motor recovery. However, the post-transcriptional mechanisms regulating AChR stability during denervation remain poorly understood. Here, we investigated the role of miR-206-3p in NMJ maintenance and muscle preservation after denervation, with a focus on its interaction with the RNA-binding protein cytoplasmic polyadenylation element binding protein 1 (Cpeb1). Using C2C12 myoblasts and a sciatic nerve transection mouse model, we demonstrate that miR-206-3p promotes myogenic differentiation, enhances AChR clustering, and preserves postsynaptic AChR morphology. miR-206-3p directly targets the 3' untranslated region of Cpeb1, suppressing its expression, as confirmed by dual-luciferase reporter assays. In vivo, adeno-associated virus-mediated overexpression of miR-206-3p delayed denervation-induced AChR fragmentation, attenuated muscle atrophy, and significantly improved motor function recovery. Conversely, Cpeb1 overexpression accelerated AChR degradation and muscle wasting, whereas co-overexpression of miR-206-3p mitigated these detrimental effects, indicating that Cpeb1 is a key downstream effector of miR-206-3p. Collectively, our findings identify the miR-206-3p/Cpeb1 axis as a previously unrecognized regulator of NMJ stability and muscle integrity after denervation, providing mechanistic insight and a potential therapeutic target for preserving neuromuscular function during prolonged denervation.