GDF-11 Protects the Traumatically Injured Spinal Cord by Suppressing Pyroptosis and Necroptosis via TFE3-Mediated Autophagy Augmentation

Oxid Med Cell Longev. 2021 Oct 19:2021:8186877. doi: 10.1155/2021/8186877. eCollection 2021.


Spinal cord injury (SCI) refers to a major worldwide cause of accidental death and disability. However, the complexity of the pathophysiological mechanism can result in less-effective clinical treatment. Growth differentiation factor 11 (GDF-11), an antiageing factor, was reported to affect the development of neurogenesis and exert a neuroprotective effect after cerebral ischaemic injury. The present work is aimed at investigating the influence of GDF-11 on functional recovery following SCI, in addition to the potential mechanisms involved. We employed a mouse model of spinal cord contusion injury and assessed functional outcomes via the Basso Mouse Scale and footprint analysis following SCI. Using western blot assays and immunofluorescence, we analysed the levels of pyroptosis, autophagy, necroptosis, and molecules related to the AMPK-TRPML1-calcineurin signalling pathway. The results showed that GDF-11 noticeably optimized function-related recovery, increased autophagy, inhibited pyroptosis, and alleviated necroptosis following SCI. Furthermore, the conducive influences exerted by GDF-11 were reversed with the application of 3-methyladenine (3MA), an autophagy suppressor, indicating that autophagy critically impacted the therapeutically related benefits of GDF-11 on recovery after SCI. In the mechanistic study described herein, GDF-11 stimulated autophagy improvement and subsequently inhibited pyroptosis and necroptosis, which were suggested to be mediated by TFE3; this effect resulted from the activity of TFE3 through the AMPK-TRPML1-calcineurin signalling cascade. Together, GDF-11 protects the injured spinal cord by suppressing pyroptosis and necroptosis via TFE3-mediated autophagy augmentation and is a potential agent for SCI therapy.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Autophagy / drug effects*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Calcineurin / metabolism
  • Disease Models, Animal
  • Female
  • Growth Differentiation Factors / pharmacology*
  • Mice
  • Mice, Inbred C57BL
  • Necroptosis / drug effects*
  • Pyroptosis / drug effects*
  • Recovery of Function
  • Signal Transduction
  • Spinal Cord / drug effects*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Spinal Cord / physiopathology
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / pathology
  • Spinal Cord Injuries / physiopathology
  • Transient Receptor Potential Channels / metabolism


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Growth Differentiation Factors
  • Mcoln1 protein, mouse
  • Transient Receptor Potential Channels
  • Tcfe3 protein, mouse
  • AMP-Activated Protein Kinases
  • Calcineurin