Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure
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消除 fukutin 揭示肌营养不良相关心力衰竭的细胞和分子病理机制
DOI：
10.1038/s41467-019-13623-2
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发表时间：
2019
影响因子：
16.6
通讯作者：
Katanosaka Yuki
中科院分区：
文献类型：
--
作者：
Ujihara Yoshihiro;Kanagawa Motoi;Mohri Satoshi;Takatsu Satomi;Kobayashi Kazuhiro;Toda Tatsushi;Naruse Keiji;Katanosaka Yuki
心力衰竭是肌营养不良症患者死亡的主要原因，但其分子病理机制尚不清楚。在这里，我们展示了缺乏福山肌营养不良症致病基因fuketn基因（Fktn）的小鼠肌营养不良症相关心肌病的详细分子发病机制。尽管cardiacFkt n消除显著降低了所有发育阶段肌膜中的α-肌营养不良聚糖糖基化和肌营养不良蛋白-糖蛋白复合物蛋白，但仅在成年后期观察到心功能不全，表明膜脆性不是心功能不全的唯一病因。在青年期，Fktn缺陷小鼠易受病理性肥大应激的影响，Akt和MEF 2-组蛋白脱乙酰基酶轴下调。AcuteFktn消除引起严重的心功能不全和加速死亡率与肌细胞收缩功能障碍和高尔基体微管网络紊乱，这是改善与秋水仙碱治疗。这些数据表明，fuketamine对于维持肌细胞生理学以预防心力衰竭至关重要，因此，结果可能导致治疗干预的策略。
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 cardiacFktnelimination 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. AcuteFktnelimination 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.