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 language | English |
|---|---|
| Article number | 5754 |
| Journal | Nature communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Dec 1 2019 |
Fingerprint
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
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 journal › Article
}
TY - JOUR
T1 - Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
AU - Ujihara, Yoshihiro
AU - Kanagawa, Motoi
AU - Mohri, Satoshi
AU - Takatsu, Satomi
AU - Kobayashi, Kazuhiro
AU - Toda, Tatsushi
AU - Naruse, Keiji
AU - Katanosaka, Yuki
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076587684&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85076587684&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-13623-2
DO - 10.1038/s41467-019-13623-2
M3 - Article
C2 - 31848331
AN - SCOPUS:85076587684
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5754
ER -