Umehara Takahiro, Murase Takehiko, Abe Yuki, Yamashita Hiromi, Shibaike Yoshinori, Kagawa Shinichiro, Yamamoto Takuma, Ikematsu Kazuya
Division of Forensic Pathology and Science, Unit of Social Medicine, Course of Medical and Dental Sciences, Graduate School of Biomedical Sciences, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan.
Center for Forensic Pathology and Science, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, Nagasaki, 852-8523, Japan.
Int J Legal Med. 2019 Mar;133(2):335-345. doi: 10.1007/s00414-018-1888-3. Epub 2018 Jun 29.
Diagnosis of fatal hypothermia is considered to be difficult in forensic practice and even if findings due to cold exposure are evident, cold exposure is not necessarily a direct cause of death. Identification of useful molecular markers for the diagnosis of fatal hypothermia has not been successful. In this study, to identify novel molecular markers that inform the diagnosis of fatal hypothermia, we focused on skeletal muscle, which plays a role in cold-induced thermogenesis in mammals. We made rat models of mild, moderate, and severe hypothermia and performed body temperature-dependent gene expression analysis in the iliopsoas muscle using next-generation sequencing (NGS). NGS showed that after severe hypothermia, the expression levels of 91 mRNAs were more than double those in mild and moderate hypothermia and control animals. Gene ontology (GO) analysis indicated that these mRNAs are involved in a number of biological processes, including response to stress and lipids, and cellular response to hypoxia. The expression of four genes [connective tissue growth factor (Ctgf), JunB proto-oncogene, AP-1 transcription factor subunit (Junb), nuclear receptor subfamily 4, group A, member 1 (Nr4a1), and Syndecan 4 (Sdc4)] and the level of one protein (CTGF) were induced only by severe hypothermia. These genes and protein are involved in muscle regeneration, tissue repair, and lipid metabolism. These results indicate that heat production to maintain body temperature in a process leading to fatal hypothermia might be performed by the iliopsoas muscle, and that Ctgf, Junb, Nr4a1, and Sdc4 genes are potential diagnostic markers for fatal hypothermia.
在法医实践中，诊断致死性体温过低被认为是困难的，即使因寒冷暴露导致的体征明显，寒冷暴露也不一定是直接死因。目前尚未成功鉴定出用于诊断致死性体温过低的有用分子标志物。在本研究中，为了鉴定有助于诊断致死性体温过低的新型分子标志物，我们聚焦于骨骼肌，其在哺乳动物的冷诱导产热中发挥作用。我们制作了轻度、中度和重度体温过低的大鼠模型，并使用下一代测序（NGS）对髂腰肌进行了体温依赖性基因表达分析。NGS结果显示，在重度体温过低后，91种mRNA的表达水平比轻度、中度体温过低以及对照动物中的表达水平高出一倍以上。基因本体（GO）分析表明，这些mRNA参与了许多生物学过程，包括对应激和脂质的反应以及细胞对缺氧的反应。只有重度体温过低会诱导4个基因[结缔组织生长因子（Ctgf）、原癌基因JunB、AP-1转录因子亚基（Junb）、核受体亚家族4 A组成员1（Nr4a1）和Syndecan 4（Sdc4）]的表达以及1种蛋白质（CTGF）的水平。这些基因和蛋白质参与肌肉再生、组织修复和脂质代谢。这些结果表明，在导致致死性体温过低的过程中，维持体温的产热可能由髂腰肌进行，并且Ctgf、Junb、Nr4a1和Sdc4基因是致死性体温过低的潜在诊断标志物。
