PT  - JOURNAL ARTICLE
AU  - Yashirogi, Shohei
AU  - Katayama, Toru
AU  - Nagao, Takemasa
AU  - Nishida, Yuya
AU  - Kioka, Hidetaka
AU  - Matsui, Tsubasa S
AU  - Saito, Shigeyoshi
AU  - Masumura, Yuki
AU  - Tsukamoto, Osamu
AU  - Kato, Hisakazu
AU  - Yazawa, Issei
AU  - Ueda, Hiromichi
AU  - Yamaguchi, Osamu
AU  - Yashiro, Kenta
AU  - Yamazaki, Satoru
AU  - Takashima, Seiji
AU  - Shintani, Yasunori
TI  - AMPK regulates cell shape of cardiomyocytes by modulating turnover of microtubules through CLIP-170
AID  - 10.1101/2020.05.29.123299
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.29.123299
4099  - http://biorxiv.org/content/early/2020/05/29/2020.05.29.123299.short
4100  - http://biorxiv.org/content/early/2020/05/29/2020.05.29.123299.full
AB  - 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 discs in the heart, a specific cell-cell junction present between cardiomyocytes. A contractile inhibitor, MYK-461, prevented the localization of AMPK at the intercalated discs, 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 discs. 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 discs.