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
N1 - Funding Information:
grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research, SENSHIN Medical Research Foundation, Suzuken Memorial Foundation, Wesco scientific promotion foundation, and a Shiseido Female Researcher Science Grant to Y.K. and Takeda Science Foundation to M.K. and Y.K.
Funding Information:
This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (grant numbers 17H02085, 18K19924 to Y.K. and 17H04740 to Y.U.), the Japan Society for the Promotion of Science Funding Program for Next Generation World-Leading Researchers (grant number 10104401 to Y.K.), the Japan Agency for Medical Research and Development (grant numbers JP17gm5810003 to Y.K. and JP17gm0810010 to M.K.), the National Center of Neurology and Psychiatry (Intramural Research Grant 29-4 to T.T.) and Grant-in-Aid for scientific Research on Innovative Areas (JP17H06421 to M.K.), MEXT. This work was supported in part by a
Publisher Copyright:
© 2019, The Author(s).
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.
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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 -