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

Abstract

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.

Elamipretide alleviates pyroptosis in traumatically injured spinal cord by inhibiting cPLA2-induced lysosomal membrane permeabilization

“…The outcomes demonstrated that SS-31 substantially reduced the expression levels of proteins associated with pyroptosis following SCI. Our group has previously explored the involvement of autophagy in SCI [ 7 , 61 , 62 ]. Basal levels of autophagy are vital for maintaining cell homeostasis and are required for neural cell function and survival.…”

“…These investigations demonstrated that SS-31 increased autophagic flux in SCI. Previous research has demonstrated that activating autophagy in the context of CNS trauma inhibits the pyroptotic death of cells [ 7 , 61 , 65 ]. The results of our experiments corroborated these observations.…”

“…AAVs may need several days to take effect in vivo, and according to previous studies [ 7 , 38 ], 2 weeks before SCI is considered an appropriate time point to carry out AAV injection. Therefore, 2 weeks before surgery, the Sham+AAV-Pla2g4a, SCI+AAV-Pla2g4a and SCI+AAV-Pla2g4a+SS-31 groups were injected with 2 µl of effective viral vectors in PBS at the T9–T10 level to a depth of 1.5 mm from the dorsal surface of the spinal cord with microsyringes.…”

“…Secondary damage manifests as neuroinflammation, ischaemia, oxidative stress, and cell death [ 4 , 5 ]. Current evidence indicates that inhibition of neuronal death and promotion of cellular organelle integrity are vital for SCI [ 6 , 7 ].…”

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

“…Clinically, the conventional neuroprotective therapies for CNS injury mainly attempt to relieve mechanical compression by surgery combined with hyperbaric oxygen therapy, high-dose methylprednisolone, nerve dehydration and other comprehensive programmes [ 6 – 8 ]. Basic research has revealed potential treatments such as growth factors, tissue engineering, cell transplantation and neuroinflammation inhibitors [ 9 – 11 ], but major breakthroughs have not yet been achieved. Although these therapeutic measures alleviate the loss of neurological function to a certain extent, the long-term prognosis of CNS injury and the recovery of neurological function are still not optimistic.…”