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LKB1 使成肌细胞中的微管不稳定，并有助于成肌细胞分化。

LKB1 destabilizes microtubules in myoblasts and contributes to myoblast differentiation.

机构信息

Center for Molecular Medicine and University of Connecticut Health Center, Farmington, Connecticut, United States of America.

出版信息

PLoS One. 2012;7(2):e31583. doi: 10.1371/journal.pone.0031583. Epub 2012 Feb 14.

DOI:10.1371/journal.pone.0031583
PMID:22348111
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3279410/
Abstract

BACKGROUND

Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified.

FINDINGS

We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMP-activated protein kinase (AMPK) and microtubule affinity regulating kinases (MARKs). LKB1 overexpression accelerated differentiation, whereas RNAi impaired it.

CONCLUSIONS

Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeletal changes required for differentiation. Transient destabilization of microtubules might be a useful strategy for enhancing and/or synchronizing myoblast differentiation.

摘要

背景

骨骼肌成肌细胞分化并融合形成多核肌管与细胞骨架的剧烈变化有关。我们发现分化的肌管中的微管高度稳定，但过早的微管稳定会阻止分化。尚未确定成肌细胞中导致微管不稳定的因素。

研究结果

我们发现，成肌细胞分化早期微管稳定性的短暂下降先于分化的肌管中最终观察到的微管稳定性。我们报告丝氨酸/苏氨酸激酶 LKB1 在微管去稳定化和成肌细胞分化中都发挥作用。LKB1 过表达在紫杉醇洗脱测定中减少微管伸长，而 LKB1 RNAi 增加了微管伸长，表明 LKB1 使成肌细胞中的微管组装不稳定。LKB1 水平和活性在成肌细胞分化过程中增加，同时激活已知的 LKB1 底物 AMP 激活的蛋白激酶 (AMPK) 和微管亲和调节激酶 (MARK)。LKB1 过表达加速了分化，而 RNAi 则损害了分化。

结论

微管稳定性的降低先于成肌细胞分化以及在肌管中观察到的最终微管稳定化。LKB1 在成肌细胞中的微管去稳定化和成肌细胞分化中发挥积极作用。这项工作提出了一个模型，即 LKB1 诱导的微管去稳定化促进了分化所需的细胞骨架变化。微管的短暂去稳定可能是增强和/或同步成肌细胞分化的有用策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/7c6ed9e92f1c/pone.0031583.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/34d84b39a01f/pone.0031583.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/f7f264b798af/pone.0031583.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/d5e39c2f48ec/pone.0031583.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/fec12497a7ca/pone.0031583.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/7c32949d4b0c/pone.0031583.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/b3ecb54263c7/pone.0031583.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/7c6ed9e92f1c/pone.0031583.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/34d84b39a01f/pone.0031583.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/f7f264b798af/pone.0031583.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/d5e39c2f48ec/pone.0031583.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/fec12497a7ca/pone.0031583.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/7c32949d4b0c/pone.0031583.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/b3ecb54263c7/pone.0031583.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dbe1/3279410/7c6ed9e92f1c/pone.0031583.g007.jpg

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