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 and Yuki Katanosaka ()
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Yoshihiro Ujihara: Okayama University
Motoi Kanagawa: Kobe University Graduate School of Medicine
Satoshi Mohri: Okayama University
Satomi Takatsu: Okayama University
Kazuhiro Kobayashi: Kobe University Graduate School of Medicine
Tatsushi Toda: Kobe University Graduate School of Medicine
Keiji Naruse: Okayama University
Yuki Katanosaka: Okayama University

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13623-2

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