Autophagy Induction Contributes to the Neuroprotective Impact of Intermittent Fasting on the Acutely Injured Spinal Cord

J Neurotrauma. 2021 Feb;38(3):373-384. doi: 10.1089/neu.2020.7166. Epub 2020 Nov 12.


Spinal cord injury (SCI) is one of the leading causes of neurological disability and death. So far, there is no satisfactory treatment for SCI, because of its complex and ill-defined pathophysiology. Recently, autophagy has been implicated as protective in acute SCI rat models. Here, we investigated the therapeutic value of a dietary intervention, namely, intermittent fasting (IF), on neuronal survival after acute SCI in rats, and its underlying mechanism related to autophagy regulation. We found remarkable improvement in both behavioral performance and neuronal survival at the injured segment of the spinal cord of animals previously subjected to IF. Western blotting revealed a marked decrease in apoptosis-related markers such as cleaved caspase 3 levels and the bax/bcl-2 ratio in the IF group, which suggested an inhibition of the intrinsic apoptosis pathway. In addition, the expression of the autophagy markers LC3-II and beclin 1 was also increased in the IF group compared with ad libitum fed animals. In parallel, IF decreased the levels of the substrate protein of autophagy, p62, indicative of an upregulation of the autophagic processes. Treatment with 3-methyladenine (3-MA), a selective inhibitor of autophagy, reversed the downregulated apoptosis-related markers by IF. Finally, IF could activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway and enhance lysosome function by upregulating transcription factor (TF)EB expression. Altogether, the present findings suggest that IF exerts a neuroprotective effect after acute SCI via the upregulation of autophagy, and further points to dietary interventions as a promising combinatorial treatment for SCI.

Keywords: autophagy flux; intermittent fasting; lysosome; neuroprotection; spinal cord injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Cell Survival
  • Disease Models, Animal
  • Fasting*
  • Male
  • Motor Activity
  • Neurons / pathology*
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function
  • Spinal Cord Injuries / diet therapy*
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology