AMP‐activated protein kinase (AMPK) is a multifunctional kinase that regulates microtubule (MT) dynamic instability through CLIP‐170 phosphorylation; however, its physiological relevance in vivo remains to be elucidated. In this study, we identified an active form of AMPK localized at the intercalated disks in the heart, a specific cell–cell junction present between cardiomyocytes. A contractile inhibitor, MYK‐461, prevented the localization of AMPK at the intercalated disks, and the effect was reversed by the removal of MYK‐461, suggesting that the localization of AMPK is regulated by mechanical stress. Time‐lapse imaging analysis revealed that the inhibition of CLIP‐170 Ser‐311 phosphorylation by AMPK leads to the accumulation of MTs at the intercalated disks. Interestingly, MYK‐461 increased the individual cell area of cardiomyocytes in CLIP‐170 phosphorylation‐dependent manner. Moreover, heart‐specific CLIP‐170 S311A transgenic mice demonstrated elongation of cardiomyocytes along with accumulated MTs, leading to progressive decline in cardiac contraction. In conclusion, these findings suggest that AMPK regulates the cell shape and aspect ratio of cardiomyocytes by modulating the turnover of MTs through homeostatic phosphorylation of CLIP‐170 at the intercalated disks.

中文翻译：

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AMPK 通过 CLIP-170 调节微管的周转来调节心肌细胞的细胞形状


AMP 激活蛋白激酶 (AMPK) 是一种多功能激酶，通过 CLIP-170 磷酸化调节微管 (MT) 动态不稳定性；然而，其在体内的生理相关性仍有待阐明。在这项研究中，我们发现了一种位于心脏闰盘（心肌细胞之间存在的特定细胞-细胞连接）处的 AMPK 活性形式。收缩抑制剂 MYK-461 阻止了 AMPK 在闰盘上的定位，并且通过去除 MYK-461 可逆转该效应，表明 AMPK 的定位受到机械应力的调节。延时成像分析显示，AMPK 对 CLIP-170 Ser-311 磷酸化的抑制导致 MT 在闰盘处积累。有趣的是，MYK-461 以 CLIP-170 磷酸化依赖性方式增加了心肌细胞的单个细胞面积。此外，心脏特异性 CLIP-170 S311A 转基因小鼠表现出心肌细胞的伸长以及 MT 的积累，导致心脏收缩逐渐减弱。总之，这些发现表明 AMPK 通过闰盘处 CLIP-170 的稳态磷酸化调节 MT 的周转来调节心肌细胞的细胞形状和纵横比。