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Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury

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Abstract

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27‐3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.

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Data Availability

All data and materials that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This study was supported by the Wenzhou Basic Public Welfare Scientific Project (Y20220936) and the National Natural Science Foundation of China (No. 82102674).

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  1. Yongli Wang and Nongtao Fang contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Yongli Wang, Nongtao Fang, Yikang Wang, Yibo Geng & Yao Li

  2. Department of Orthopaedics, Huzhou Central Hospital, Huzhou Basic and Clinical Translation of Orthopaedics Key Laboratory, Huzhou, Zhejiang, China

    Yongli Wang

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Contributions

YL contributed to the conception of the study. YoW analyzed the data and wrote the manuscript. NF and YiW performed Western blotting and staining experiments. YG performed animal modeling and contributed new reagents and modified the manuscript. All the authors contributed to the article and approve of the submitted version.

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Correspondence to Yao Li.

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12035_2024_3936_MOESM1_ESM.tif

Supplementary file1 Supplementary figure 1. HS024 treatment inhibits MC4R activation mediated neural growth. (A-B) Representative neuron morphology stained with Tuj1 and quantitative analysis of axonal length of neuron in each group, neurons were treated with TBHP (50nM), RO27-3225 (250nM), co-treated TBHP and RO27-3225, or co-treated TBHP, RO27-3225 and HS024 (100nM) for 6 hours, n = 6, scale bar = 100 μm. Significance: *P<0.05, **P<0.01, ***P<0.001, and NS (not significant). Data were expressed as means ± SD. (TIF 5280 KB)

12035_2024_3936_MOESM2_ESM.tif

Supplementary file2 Supplementary figure 2. AIM2 has no effect on MC4R expression. Western blotting and quantification of the MC4R level in WT and AIM2 KO mice at 3 days after SCI, n = 5. β-Tubulin was the loading control. Significance: *P<0.05, **P<0.01, ***P<0.001, and NS (not significant). Data were expressed as means ± SD. (TIF 2387 KB)

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Wang, Y., Fang, N., Wang, Y. et al. Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-03936-9

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