Cargando…

CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation

Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade;...

Descripción completa

Detalles Bibliográficos
Autores principales: Ye, Cheng, Zhang, Duo, Zhao, Lei, Li, Yan, Yao, Xiaohan, Wang, Hui, Zhang, Shengjie, Liu, Wei, Cao, Hongchao, Yu, Shuxian, Wang, Yucheng, Jiang, Jingjing, Li, Xihua, Ying, Hao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085727/
https://www.ncbi.nlm.nih.gov/pubmed/27783047
http://dx.doi.org/10.3390/ijms17101695
_version_ 1782463631099691008
author Ye, Cheng
Zhang, Duo
Zhao, Lei
Li, Yan
Yao, Xiaohan
Wang, Hui
Zhang, Shengjie
Liu, Wei
Cao, Hongchao
Yu, Shuxian
Wang, Yucheng
Jiang, Jingjing
Wang, Hui
Li, Xihua
Ying, Hao
author_facet Ye, Cheng
Zhang, Duo
Zhao, Lei
Li, Yan
Yao, Xiaohan
Wang, Hui
Zhang, Shengjie
Liu, Wei
Cao, Hongchao
Yu, Shuxian
Wang, Yucheng
Jiang, Jingjing
Wang, Hui
Li, Xihua
Ying, Hao
author_sort Ye, Cheng
collection PubMed
description Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration.
format Online
Article
Text
id pubmed-5085727
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-50857272016-11-01 CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation Ye, Cheng Zhang, Duo Zhao, Lei Li, Yan Yao, Xiaohan Wang, Hui Zhang, Shengjie Liu, Wei Cao, Hongchao Yu, Shuxian Wang, Yucheng Jiang, Jingjing Wang, Hui Li, Xihua Ying, Hao Int J Mol Sci Article Skeletal muscle has a major role in locomotion and muscle disorders are associated with poor regenerative efficiency. Therefore, a deeper understanding of muscle regeneration is needed to provide a new insight for new therapies. CaMKK2 plays a role in the calcium/calmodulin-dependent kinase cascade; however, its role in skeletal muscle remains unknown. Here, we found that CaMKK2 expression levels were altered under physiological and pathological conditions including postnatal myogensis, freeze or cardiotoxin-induced muscle regeneration, and Duchenne muscular dystrophy. Overexpression of CaMKK2 suppressed C2C12 myoblast proliferation and differentiation, while inhibition of CaMKK2 had opposite effect. We also found that CaMKK2 is able to activate AMPK in C2C12 myocytes. Inhibition of AMPK could attenuate the effect of CaMKK2 overexpression, while AMPK agonist could abrogate the effect of CaMKK2 knockdown on C2C12 cell differentiation and proliferation. These results suggest that CaMKK2 functions as an AMPK kinase in muscle cells and AMPK mediates the effect of CaMKK2 on myoblast proliferation and differentiation. Our data also indicate that CaMKK2 might inhibit myoblast proliferation through AMPK-mediated cell cycle arrest by inducing cdc2-Tyr15 phosphorylation and repress differentiation through affecting PGC1α transcription. Lastly, we show that overexpressing CaMKK2 in the muscle of mice via electroporation impaired the muscle regeneration during freeze-induced injury, indicating that CaMKK2 could serve as a potential target to treat patients with muscle injury or myopathies. Together, our study reveals a new role for CaMKK2 as a negative regulator of myoblast differentiation and proliferation and sheds new light on the molecular regulation of muscle regeneration. MDPI 2016-10-24 /pmc/articles/PMC5085727/ /pubmed/27783047 http://dx.doi.org/10.3390/ijms17101695 Text en © 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ye, Cheng
Zhang, Duo
Zhao, Lei
Li, Yan
Yao, Xiaohan
Wang, Hui
Zhang, Shengjie
Liu, Wei
Cao, Hongchao
Yu, Shuxian
Wang, Yucheng
Jiang, Jingjing
Wang, Hui
Li, Xihua
Ying, Hao
CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation
title CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation
title_full CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation
title_fullStr CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation
title_full_unstemmed CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation
title_short CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation
title_sort camkk2 suppresses muscle regeneration through the inhibition of myoblast proliferation and differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085727/
https://www.ncbi.nlm.nih.gov/pubmed/27783047
http://dx.doi.org/10.3390/ijms17101695
work_keys_str_mv AT yecheng camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT zhangduo camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT zhaolei camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT liyan camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT yaoxiaohan camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT wanghui camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT zhangshengjie camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT liuwei camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT caohongchao camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT yushuxian camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT wangyucheng camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT jiangjingjing camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT wanghui camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT lixihua camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation
AT yinghao camkk2suppressesmuscleregenerationthroughtheinhibitionofmyoblastproliferationanddifferentiation