Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
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 α-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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Nature communications - 10(2019), 1 vom: 17. Dez., Seite 5754 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ujihara, Yoshihiro [VerfasserIn] |
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| Links: |
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| Themen: |
146888-27-9 |
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| Anmerkungen: |
Date Completed 06.04.2020 Date Revised 10.01.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-019-13623-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM304491497 |
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| 245 | 1 | 0 | |a Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 α-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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a Kanagawa, Motoi |e verfasserin |4 aut | |
| 700 | 1 | |a Mohri, Satoshi |e verfasserin |4 aut | |
| 700 | 1 | |a Takatsu, Satomi |e verfasserin |4 aut | |
| 700 | 1 | |a Kobayashi, Kazuhiro |e verfasserin |4 aut | |
| 700 | 1 | |a Toda, Tatsushi |e verfasserin |4 aut | |
| 700 | 1 | |a Naruse, Keiji |e verfasserin |4 aut | |
| 700 | 1 | |a Katanosaka, Yuki |e verfasserin |4 aut | |
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