The skeletal muscles of mice infected with Plasmodium berghei and Plasmodium chabaudi reveal a crosstalk between lipid mediators and gene expression
The skeletal muscles of mice infected with Plasmodium berghei and Plasmodium chabaudi reveal a crosstalk between lipid mediators and gene expression
复制标题
DOI：
10.1186/s12936-020-03332-3
复制
发表时间：
2020-07-14
期刊：
影响因子：
3
通讯作者：
Brotto, Marco
中科院分区：
文献类型：
--
作者：
Marrelli, Mauro Toledo;Wang, Zhiying;Brotto, Marco
背景疟疾是世界上最流行的传染病之一，有 32 亿人面临风险。疟疾会导致脾肿大和其他器官（包括骨骼肌）损伤。骨骼肌占人体近 50%，主要负责整体新陈代谢的调节和调节。为了制定有效的预防措施和/或治疗方法，了解疟疾如何损害肌肉至关重要。利用临床前动物模型，研究疟原虫感染影响小鼠骨骼肌的潜在分子机制。方法采用Mouse Signal Transduction Pathway Finder PCR Array监测伯氏疟原虫和恰鲍迪疟原虫感染小鼠骨骼肌中10条重要信号通路的基因表达变化。然后，应用一种新的靶向脂质组学方法，使用液相色谱和串联质谱 (LC-MS/MS) 来分析 158 种脂质信号传导介质 (LM)，其中大部分是源自花生四烯酸 (AA)、二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 的类二十烷酸。最后，对与骨骼肌炎症、氧化应激和组织愈合直接相关的 16 个关键 LM 进行了定量。结果结果表明，疟原虫感染改变的关键基因的表达与炎症、氧化应激和萎缩有关。为了支持基因分析结果，脂质组学揭示了骨骼肌中与炎症反应直接相关的 LM 浓度较高，而对解决炎症和组织修复至关重要的 LM 水平显着降低。结论该结果为疟疾引起的肌肉损伤的分子机制提供了新的见解，并揭示了调节疟疾肌肉炎症的潜在机制。这些临床前研究应有助于未来的人类临床研究，旨在监测疾病进展和制定具体干预措施，以预防和减轻对骨骼肌功能的长期慢性影响。
BackgroundMalaria is one of the most prevalent infectious disease in the world with 3.2 billion humans at risk. Malaria causes splenomegaly and damage in other organs including skeletal muscles. Skeletal muscles comprise nearly 50% of the human body and are largely responsible for the regulation and modulation of overall metabolism. It is essential to understand how malaria damages muscles in order to develop effective preventive measures and/or treatments. Using a pre-clinical animal model, the potential molecular mechanisms of Plasmodium infection affecting skeletal muscles of mice were investigated.MethodsMouse Signal Transduction Pathway Finder PCR Array was used to monitor gene expression changes of 10 essential signalling pathways in skeletal muscles from mice infected with Plasmodium berghei and Plasmodium chabaudi. Then, a new targeted-lipidomic approach using liquid chromatography with tandem mass spectrometry (LC-MS/MS) to profile 158 lipid signalling mediators (LMs), mostly eicosanoids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was applied. Finally, 16 key LMs directly associated with inflammation, oxidative stress, and tissue healing in skeletal muscles, were quantified.ResultsThe results showed that the expression of key genes altered by Plasmodium infection is associated with inflammation, oxidative stress, and atrophy. In support to gene profiling results, lipidomics revealed higher concentrations of LMs in skeletal muscles directly related to inflammatory responses, while on the levels of LMs crucial in resolving inflammation and tissue repair reduced significantly.ConclusionThe results provide new insights into the molecular mechanisms of malaria-induced muscle damage and revealed a potential mechanism modulating inflammation in malarial muscles. These pre-clinical studies should help with future clinical studies in humans aimed at monitoring of disease progression and development of specific interventions for the prevention and mitigation of long-term chronic effects on skeletal muscle function.