Integrated transcriptomic and metabolomic profiling reveals dysregulation of purine metabolism during the acute phase of spinal cord injury in rats

Spinal cord injury (SCI) results in drastic dysregulation of microenvironmental metabolism during the acute phase, which greatly affects neural recovery. A better insight into the potential molecular pathways of metabolic dysregulation by multi-omics analysis could help to reveal targets that promote nerve repair and regeneration in the future. In the present study, we extracted RNA and metabolites from the injured spinal cord of rats during the acute phase and then the transcriptomic and metabolomic data were integrated in SCI model of rat to reveal the underlying molecular pathways of microenvironmental metabolic dysregulation. Metabolomics analysis showed that 360 metabolites were highly altered during the acute phase of SCI, of which 310 were up-regulated and 50 were down-regulated, and bioinformatics analysis revealed that these differential metabolites were mainly enriched in arginine and proline metabolism, D-glutamine and D-glutamate metabolism, purine metabolism, biosynthesis of unsaturated fatty acids. Transcriptomics results showed that 5963 genes were clearly altered, of which 2848 genes were up-regulated and 3115 genes were down-regulated, and these differentially expressed genes were mainly involved in response to stimulus, metabolic process, immune system process. Surprisingly, the Integrative analysis revealed significant dysregulation of purine metabolism at both transcriptome and metabolome levels in the acute phase of SCI, with 48 differential genes and 16 differential metabolites involved. Further analysis indicated that dysregulation of purine metabolism could seriously affect the energy metabolism of the injured microenvironment and increase oxidative stress as well as other responses detrimental to nerve repair and regeneration. On the whole, we have for the first time combined transcriptomics and metabolomics to systematically analyze the potential molecular pathways of metabolic dysregulation in the acute phase of SCI, which will contribute to broaden our understanding of the sophisticated molecular mechanisms of SCI, in parallel with serving as a foundation for future studies of neural repair and regeneration after SCI.

脊髓损伤（Spinal Cord Injury, SCI）会在急性期引发微环境代谢的严重失调，极大影响神经功能恢复。通过多组学分析深入解析代谢失调的潜在分子通路，未来有望揭示促进神经修复与再生的潜在靶点。本研究中，我们从急性期大鼠损伤脊髓中提取了RNA与代谢物，并整合大鼠SCI模型的转录组与代谢组数据，以解析微环境代谢失调的潜在分子通路。代谢组学分析显示，SCI急性期共有360种代谢物发生显著变化，其中310种上调、50种下调；生物信息学分析表明，这些差异代谢物主要富集于精氨酸与脯氨酸代谢、D-谷氨酰胺与D-谷氨酸代谢、嘌呤代谢以及不饱和脂肪酸生物合成通路。转录组分析结果显示，共有5963个基因表达发生显著变化，其中2848个基因上调、3115个基因下调；这些差异表达基因主要参与应激反应、代谢过程以及免疫系统过程。令人意外的是，整合分析揭示SCI急性期的嘌呤代谢在转录组与代谢组层面均存在显著失调，涉及48个差异基因与16个差异代谢物。进一步分析表明，嘌呤代谢失调会严重影响损伤微环境的能量代谢，并加剧氧化应激及其他不利于神经修复与再生的病理反应。总体而言，本研究首次结合转录组学与代谢组学，系统解析了SCI急性期代谢失调的潜在分子通路，这不仅有助于加深我们对SCI复杂分子机制的理解，同时也可为未来脊髓损伤后神经修复与再生的相关研究奠定基础。