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Ujihara, Yoshihiro Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Kanagawa, Motoi Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine
Mohri, Satoshi Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Takatsu, Satomi Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
Kobayashi, Kazuhiro Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine
Toda, Tatsushi Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine
Naruse, Keiji Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Katanosaka, Yuki Department of Cardiovascular Physiology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University ORCID Kaken ID publons researchmap
Abstract
Heart failure is the major cause of death for muscular dystrophy patients, however, the molecular pathomechanism remains unknown. Here, we show the detailed molecular pathogenesis of muscular dystrophy-associated cardiomyopathy in mice lacking the fukutin gene (Fktn), the causative gene for Fukuyama muscular dystrophy. Although cardiac Fktn elimination markedly reduced alpha-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins in sarcolemma at all developmental stages, cardiac dysfunction was observed only in later adulthood, suggesting that membrane fragility is not the sole etiology of cardiac dysfunction. During young adulthood, Fktn-deficient mice were vulnerable to pathological hypertrophic stress with downregulation of Akt and the MEF2-histone deacetylase axis. Acute Fktn elimination caused severe cardiac dysfunction and accelerated mortality with myocyte contractile dysfunction and disordered Golgi-microtubule networks, which were ameliorated with colchicine treatment. These data reveal fukutin is crucial for maintaining myocyte physiology to prevent heart failure, and thus, the results may lead to strategies for therapeutic intervention.
Published Date
2019-12-17
Publication Title
Nature Communications
Volume
volume10
Publisher
Nature Publishing Group
Start Page
5754
ISSN
2041-1723
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© The Author(s) 2019
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publisher
PubMed ID
DOI
Web of Science KeyUT
Related Url
isVersionOf https://doi.org/10.1038/s41467-019-13623-2
License
http://creativecommons.org/licenses/by/4.0/
Funder Name
Ministry of Education, Culture, Sports, Science and Technology
助成番号
17H02085
18K19924
17H04740
10104401
17H06421