Improved Motor Nerve Regeneration by SIRT1/Hif1a-Mediated Autophagy.

David Romeo-Guitart,Joaquim Forés,Tatiana Leiva-Rodriguez,Caty Casas

doi:10.3390/cells8111354

Abstract

Complete restoring of functional connectivity between neurons or target tissue after traumatic lesions is still an unmet medical need. Using models of nerve axotomy and compression, we investigated the effect of autophagy induction by genetic and pharmacological manipulation on motor nerve regeneration. ATG5 or NAD+-dependent deacetylase sirtuin-1 (SIRT1) overexpression on spinal motoneurons stimulates mTOR-independent autophagy and facilitates a growth-competent state improving motor axonal regeneration with better electromyographic records after nerve transection and suture. In agreement with this, using organotypic spinal cord cultures and the human cell line SH-SY5Y, we observed that the activation of SIRT1 and autophagy by NeuroHeal increased neurite outgrowth and length extension and that this was mediated by downstream HIF1a. To conclude, SIRT1/Hifα-dependent autophagy confers a more pro-regenerative phenotype to motoneurons after peripheral nerve injury. Altogether, we provide evidence showing that autophagy induction by SIRT1/Hifα activation or NeuroHeal treatment is a novel therapeutic option for improving motor nerve regeneration and functional recovery after injury.

Highlights

Peripheral nerve injury (PNI) is caused by traffic accidents, lesions at home, or at the workplace, which may result in a partial or total loss of motor function or sensory perception [1]
In order to ascertain whether autophagy induction was important in motor nerve regeneration, we aimed to investigate the potential to shift MNs to a growth-competent state by ATG5 overexpression, previously shown to induce autophagy [25]
Considering that autophagy can be triggered by AMPK as an mTOR independent mechanism [29], we investigated whether downstream SIRT1 activation that regulates the formation of autophagic vacuole may improve regeneration [30]

Summary

Introduction

Peripheral nerve injury (PNI) is caused by traffic accidents, lesions at home, or at the workplace, which may result in a partial or total loss of motor function or sensory perception [1]. At clinics, there is no coadjuvant treatment in use to promote nerve regeneration. For this purpose, our group has recently proposed a promising compound named NeuroHeal [6,7]. Our group has recently proposed a promising compound named NeuroHeal [6,7] It was designed using a network-centric approach and artificial intelligence and proved to be neuroprotective and accelerate nerve regeneration in several rodent models of axotomy [6,7]. NeuroHeal is formed by a combination of two FDA-approved drugs: acamprosate and

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