在纤维细胞中,Mmp14对于母体体内稳定和昼夜节律是必需的
Ching-Yan Chloé Yeung1, Richa Garva2, Adam Pickard2
1Wellcome Centre for Cell-Matrix Research, Faculty of Biology, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PT, UK; Institute of Sports Medicine Copenhagen, Department of Orthopedic Surgery, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; Center for Healthy Aging, Department of Clinical Medicine, University of Copenhagen, Denmark.
生物钟通过MT1-MMP调节肌原蛋白合成. 破坏这种酶会导致肌的混乱和节奏蛋白质表达的丧失,影响原交叉连接和纤维细胞的昼夜功能.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 时间生物学 时间生物学
背景情况:
- 昼夜时钟影响肌细胞外基质的组成.
- 原纤维的组装和去除的精确机制尚未完全理解.
研究的目的:
- 研究膜I型矩阵金属蛋白酶 (MT1-MMP) 在肌原蛋白的昼夜调节中的作用.
- 为了确定MT1-MMP缺乏对肌结构和母体体的影响.
主要方法:
- 产生了Mmp14条件淘汰赛 (CKO) 的小鼠,使用tamoxifen诱导的Cre-lox系统.
- 利用质谱和高压色谱分析肌蛋白质组和原交联.
- 使用CRISPR-Cas9来评估培养纤维细胞中的MT1-MMP功能.
主要成果:
- 由于积累了狭窄的原纤维,Mmp14 KO小鼠表现出肌变厚,背部曲和超结构失调.
- 丧失MT1-MMP破坏了176种蛋白质的昼夜调节,包括高和非节律的原交联酶 (LOXL1,LH1).
- 纤维细胞中的MT1-MMP缺乏消除了第2期 (PER2) 节律性;MT1-MMP有效地分裂了可溶性原-1,但没有预先组装的纤维.
结论:
- 循环时钟调节的MT1-MMP对于肌中直径小的原纤维的节奏合成至关重要.
- MT1-MMP 缺乏会破坏原交联,肌超结构,以及肌纤维细胞内的昼夜时钟.
- 这项研究阐明了一种关键的分子机制,它将昼夜节律与肌细胞外矩阵平衡联系起来.
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