CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation.
CaMKK2 Suppresses Muscle Regeneration through the Inhibition of Myoblast Proliferation and Differentiation.
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CaMKK2 通过抑制成肌细胞增殖和分化来抑制肌肉再生
DOI：
10.3390/ijms17101695
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发表时间：
2016-10-24
影响因子：
5.6
通讯作者：
Ying H
中科院分区：
文献类型：
--
作者：
Ye C;Zhang D;Zhao L;Li Y;Yao X;Wang H;Zhang S;Liu W;Cao H;Yu S;Wang Y;Jiang J;Wang H;Li X;Ying H
骨骼肌在运动中发挥着重要作用，肌肉疾病与再生效率差有关。因此，需要对肌肉再生有更深入的了解，以便为新疗法提供新的见解。 CaMKK2 在钙/钙调蛋白依赖性激酶级联中发挥作用；然而，它在骨骼肌中的作用仍然未知。在这里，我们发现 CaMKK2 表达水平在生理和病理条件下发生改变，包括出生后肌生成、冷冻或心脏毒素诱导的肌肉再生和杜氏肌营养不良。 CaMKK2的过表达抑制C2C12成肌细胞的增殖和分化，而抑制CaMKK2则具有相反的作用。我们还发现 CaMKK2 能够激活 C2C12 肌细胞中的 AMPK。抑制 AMPK 可以减弱 CaMKK2 过表达的影响，而 AMPK 激动剂可以消除 CaMKK2 敲低对 C2C12 细胞分化和增殖的影响。这些结果表明，CaMKK2 在肌肉细胞中充当 AMPK 激酶，并且 AMPK 介导 CaMKK2 对成肌细胞增殖和分化的影响。我们的数据还表明，CaMKK2 可能通过诱导 cdc2-Tyr15 磷酸化，通过 AMPK 介导的细胞周期停滞来抑制成肌细胞增殖，并通过影响 PGC1α 转录来抑制分化。最后，我们发现通过电穿孔在小鼠肌肉中过度表达 CaMKK2 会损害冷冻诱导损伤期间的肌肉再生，这表明 CaMKK2 可以作为治疗肌肉损伤或肌病患者的潜在靶点。总之，我们的研究揭示了 CaMKK2 作为成肌细胞分化和增殖的负调节因子的新作用，并为肌肉再生的分子调节提供了新的线索。
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.
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影响因子：
4.6
作者：
Kharraz Y;Guerra J;Mann CJ;Serrano AL;Muñoz-Cánoves P
通讯作者：
Muñoz-Cánoves P
影响因子：
14.9
作者：
Cisneros-Barroso E;Yance-Chávez T;Kito A;Sugiura R;Gómez-Hierro A;Giménez-Zaragoza D;Aligue R
通讯作者：
Aligue R
影响因子：
5.5
作者：
Fu, Xing;Zhao, Jun-Xing;Du, Min
通讯作者：
Du, Min
影响因子：
7
作者：
Chin, ER
通讯作者：
Chin, ER
影响因子：
4.8
作者：
Fu, Xing;Zhu, Mei-Jun;Du, Min
通讯作者：
Du, Min