Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325027, China.
Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China.
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.
脊髓损伤（SCI）是全球范围内导致意外死亡和残疾的主要原因之一。然而，其复杂的病理生理机制导致临床治疗效果不佳。生长分化因子 11（GDF-11）是一种抗衰老因子，据报道，它可以影响神经发生的发育，并在脑缺血损伤后发挥神经保护作用。本研究旨在探讨 GDF-11 对 SCI 后功能恢复的影响及其潜在机制。我们采用小鼠脊髓挫伤损伤模型，通过 Basso 小鼠量表和足迹分析评估 SCI 后的功能结果。通过 Western blot 分析和免疫荧光，我们分析了细胞焦亡、自噬、坏死性凋亡以及与 AMPK-TRPML1-钙调神经磷酸酶信号通路相关的分子的水平。结果表明，GDF-11 明显优化了 SCI 后的功能相关恢复，增加了自噬，抑制了细胞焦亡，减轻了坏死性凋亡。此外，用自噬抑制剂 3-甲基腺嘌呤（3MA）处理后，GDF-11 发挥的有利影响被逆转，表明自噬对 GDF-11 治疗 SCI 后恢复的治疗相关益处具有重要影响。在本文描述的机制研究中，GDF-11 通过 TFE3 刺激自噬改善，进而抑制细胞焦亡和坏死性凋亡，这是由 TFE3 通过 AMPK-TRPML1-钙调神经磷酸酶信号级联的活性介导的。总之，GDF-11 通过 TFE3 介导的自噬增强抑制细胞焦亡和坏死性凋亡来保护损伤的脊髓，是治疗 SCI 的潜在药物。
