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敲除人源心肌细胞中的 MYOM1 会通过损害钙稳态导致心肌萎缩。

Knockout of MYOM1 in human cardiomyocytes leads to myocardial atrophy via impairing calcium homeostasis.

机构信息

Department of Cardiology, Peking University Third Hospital, Beijing, China.

Beijing Lab for Cardiovascular Precision Medicine, Anzhen Hospital, Capital Medical University, Beijing, China.

出版信息

J Cell Mol Med. 2021 Feb;25(3):1661-1676. doi: 10.1111/jcmm.16268. Epub 2021 Jan 15.

DOI:10.1111/jcmm.16268
PMID:33452765
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7875908/
Abstract

Myomesin-1 (encoded by MYOM1 gene) is expressed in almost all cross-striated muscles, whose family (together with myomesin-2 and myomesin-3) helps to cross-link adjacent myosin to form the M-line in myofibrils. However, little is known about its biological function, causal relationship and mechanisms underlying the MYOM1-related myopathies (especially in the heart). Regrettably, there is no MYMO1 knockout model for its study so far. A better and further understanding of MYOM1 biology is urgently needed. Here, we used CRISPR/Cas9 gene-editing technology to establish an MYOM1 knockout human embryonic stem cell line (MYOM1 hESC), which was then differentiated into myomesin-1 deficient cardiomyocytes (MYOM1 hESC-CMs) in vitro. We found that myomesin-1 plays an important role in sarcomere assembly, contractility regulation and cardiomyocytes development. Moreover, myomesin-1-deficient hESC-CMs can recapitulate myocardial atrophy phenotype in vitro. Based on this model, not only the biological function of MYOM1, but also the aetiology, pathogenesis, and potential treatments of myocardial atrophy caused by myomesin-1 deficiency can be studied.

摘要

肌球蛋白结合蛋白 1（由 MYOM1 基因编码）几乎在所有横纹肌中表达，其家族（与肌球蛋白结合蛋白 2 和肌球蛋白结合蛋白 3 一起）有助于将相邻肌球蛋白交联，在肌原纤维中形成 M 线。然而，关于其生物学功能、因果关系及其在与 MYOM1 相关的肌病（尤其是心脏）中的机制知之甚少。遗憾的是，迄今为止还没有用于研究的 MYMO1 敲除模型。迫切需要对 MYOM1 生物学有更好和更深入的了解。在这里，我们使用 CRISPR/Cas9 基因编辑技术建立了 MYOM1 敲除人胚胎干细胞系（MYOM1 hESC），然后在体外将其分化为肌球蛋白结合蛋白 1 缺失的心肌细胞（MYOM1 hESC-CMs）。我们发现肌球蛋白结合蛋白 1在肌节组装、收缩调节和心肌细胞发育中发挥重要作用。此外，肌球蛋白结合蛋白 1 缺失的 hESC-CMs 可以在体外再现心肌萎缩表型。基于该模型，不仅可以研究 MYOM1 的生物学功能，还可以研究肌球蛋白结合蛋白 1 缺失引起的心肌萎缩的病因、发病机制和潜在治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/b2f98d816e5f/JCMM-25-1661-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/48a87a7bd50a/JCMM-25-1661-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/1cab4967b63d/JCMM-25-1661-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/9ec7323f1f2b/JCMM-25-1661-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/93a10bd6d197/JCMM-25-1661-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/e5c03ada77fe/JCMM-25-1661-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/b2f98d816e5f/JCMM-25-1661-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/48a87a7bd50a/JCMM-25-1661-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/1cab4967b63d/JCMM-25-1661-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/9ec7323f1f2b/JCMM-25-1661-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/93a10bd6d197/JCMM-25-1661-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/e5c03ada77fe/JCMM-25-1661-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fd13/7875908/b2f98d816e5f/JCMM-25-1661-g006.jpg

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