Decreased YAP activity reduces proliferative ability in human induced pluripotent stem cell of duchenne muscular dystrophy derived cardiomyocytes

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration accompanied by dilated cardiomyopathy. Recently, abnormality of yes-associated protein (YAP) has been reported as the pathogenesis of muscle degeneration of DMD; however YAP activity remains unclear in dystrophic h...

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Bibliographic Details
Published in:	Scientific reports 2021-05, Vol.11 (1), p.10351-10351, Article 10351
Main Authors:	Yasutake, Hideki, Lee, Jong-Kook, Hashimoto, Akihito, Masuyama, Kiyoshi, Li, Jun, Kuramoto, Yuki, Higo, Shuichiro, Hikoso, Shungo, Hidaka, Kyoko, Naito, Atsuhiko T, Miyagawa, Shigeru, Sawa, Yoshiki, Komuro, Issei, Sakata, Yasushi
Format:	Article
Language:	eng
Subjects:	Actin Cardiomyocytes Cardiomyopathy CRISPR Degeneration Dilated cardiomyopathy Duchenne's muscular dystrophy Gene deletion Genomes Inhibitory postsynaptic potentials Lysophosphatidic acid Mechanotransduction Muscular dystrophy Nuclear transport Pathogenesis Pluripotency Stem cells Yes-associated protein
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Summary:	Duchenne muscular dystrophy (DMD) is characterized by progressive muscle degeneration accompanied by dilated cardiomyopathy. Recently, abnormality of yes-associated protein (YAP) has been reported as the pathogenesis of muscle degeneration of DMD; however YAP activity remains unclear in dystrophic heart of DMD. Herein, we investigated YAP activity using disease-specific induced pluripotent stem cell (iPSC) derived cardiomyocytes (CMs) in DMD. DMD-iPSCs were generated from DMD patient with exon 48-54 deletion in DMD, and genome-edited (Ed)-DMD-iPSCs with in-frame (Ed-DMD-iPSCs) were created using CRISPR/Cas9. Nuclear translocation of YAP [nuclear (N)/cytoplasmic (C) ratio] was significantly lower in DMD-iPSC-CMs than in Ed-DMD-iPSC-CMs. In addition, Ki67 expression, indicating proliferative ability, was significantly lower in DMD-iPSC-CMs than Ed-DMD-iPSC-CMs. Therefore, immunofluorescent staining showed that actin stress fibers associated with YAP activity by mechanotransduction were disorganized in DMD-iPSC-CMs. Lysophosphatidic acid (LPA), a known lipid mediator on induction of actin polymerization, significantly increased YAP activity and actin dynamics in DMD-iPSC-CMs using live cell imaging. These results suggested that altered YAP activity due to impaired actin dynamics reduced proliferative ability in DMD-iPSC-CMs. Hence, decreased YAP activity in dystrophic heart may contribute to DMD-cardiomyopathy pathogenesis.
ISSN:	2045-2322 2045-2322