AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP-170

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. Synopsis Mechanical stress elicited by the heart contractility promotes AMPK localization to the intercalated discs, where AMPK regulates microtubule dynamics and cardiomyocyte function. Activated AMPK localizes at the intercalated discs in the heart, a specific cell-cell junction present between cardiomyocytes. Cardiomyocyte contractility is required for AMPK localization to the intercalated discs. Inhibition of CLIP-170 phosphorylation by AMPK leads to the accumulation of microtubules at the intercalated discs. Heart-specific phospho-deficient CLIP-170 transgenic mice results in elongation of cardiomyocytes along with accumulated MTs, leading to progressive decline in cardiac contraction. Graphical Abstract Mechanical stress elicited by the heart contractility promotes AMPK localization to the intercalated discs, where AMPK regulates microtubule dynamics and cardiomyocyte function.