Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

Yoshihiro Ujihara, Motoi Kanagawa, Satoshi Mohri, Satomi Takatsu, Kazuhiro Kobayashi, Tatsushi Toda, Keiji Naruse, Yuki Katanosaka

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Article number5754
JournalNature communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

Muscular Dystrophies
genes
elimination
Heart Failure
Genes
muscle cells
Muscle Cells
mice
colchicine
Walker-Warburg Syndrome
Dystroglycans
etiology
Glycosylation
pathogenesis
Sarcolemma
Dystrophin
physiology
Histone Deacetylases
mortality
Physiology

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Ujihara, Y., Kanagawa, M., Mohri, S., Takatsu, S., Kobayashi, K., Toda, T., ... Katanosaka, Y. (2019). Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure. Nature communications, 10(1), [5754]. https://doi.org/10.1038/s41467-019-13623-2

Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure. / Ujihara, Yoshihiro; Kanagawa, Motoi; Mohri, Satoshi; Takatsu, Satomi; Kobayashi, Kazuhiro; Toda, Tatsushi; Naruse, Keiji; Katanosaka, Yuki.

In: Nature communications, Vol. 10, No. 1, 5754, 01.12.2019.

Research output: Contribution to journalArticle

Ujihara, Yoshihiro ; Kanagawa, Motoi ; Mohri, Satoshi ; Takatsu, Satomi ; Kobayashi, Kazuhiro ; Toda, Tatsushi ; Naruse, Keiji ; Katanosaka, Yuki. / Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure. In: Nature communications. 2019 ; Vol. 10, No. 1.
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