A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells
A Skeletal Muscle Model of Infantile-onset Pompe Disease with Patient-specific iPS Cells
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使用患者特异性 iPS 细胞建立婴儿型庞贝氏症骨骼肌模型
DOI：
10.1038/s41598-017-14063-y
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发表时间：
2017
影响因子：
4.6
通讯作者：
Toshio Heike & Hidetoshi Sakurai
中科院分区：
文献类型：
--
作者：
Takeshi Yoshida;Tomonari Awaya;Tatsuya Jonouchi;Ryo Kimura;Shigemi Kimura;Takumi Era;Toshio Heike & Hidetoshi Sakurai
庞贝病是由先天性溶酶体酸α-葡萄糖苷酶（GAA）缺陷引起的，其特征是溶酶体糖原主要积聚在骨骼肌和心脏。重症庞贝病（IOPD）患者在婴儿期早期表现为全身肌肉无力和心力衰竭。它们活不过两年。重组人GAA （rhGAA）酶替代疗法提高了生存率，但与其他器官相比，其对骨骼肌的作用不足。此外，骨骼肌损伤在IOPD中的病理机制尚不清楚。在这里，我们从IOPD患者中获得诱导多能干细胞（iPSCs）并将其分化为肌细胞。分化后的肌细胞表现为溶酶体糖原积累，rhGAA可剂量依赖性地恢复溶酶体糖原积累。我们进一步证明，哺乳动物/机制靶雷帕霉素复合物1 （mTORC1）活性在IOPD ipsc来源的肌细胞中受损。综合代谢组学和转录组学分析表明mtorc1相关信号的紊乱，包括能量状态恶化和线粒体氧化功能抑制。综上所述，我们成功地利用患者特异性iPSCs建立了一种体外骨骼肌模型。mTORC1信号紊乱可能与IOPD骨骼肌损伤的发病机制有关，可能是Pompe病的潜在治疗靶点。
Pompe disease is caused by an inborn defect of lysosomal acid α-glucosidase (GAA) and is characterized by lysosomal glycogen accumulation primarily in the skeletal muscle and heart. Patients with the severe type of the disease, infantile-onset Pompe disease (IOPD), show generalized muscle weakness and heart failure in early infancy. They cannot survive over two years. Enzyme replacement therapy with recombinant human GAA (rhGAA) improves the survival rate, but its effect on skeletal muscle is insufficient compared to other organs. Moreover, the patho-mechanism of skeletal muscle damage in IOPD is still unclear. Here we generated induced pluripotent stem cells (iPSCs) from patients with IOPD and differentiated them into myocytes. Differentiated myocytes showed lysosomal glycogen accumulation, which was dose-dependently rescued by rhGAA. We further demonstrated that mammalian/mechanistic target of rapamycin complex 1 (mTORC1) activity was impaired in IOPD iPSC-derived myocytes. Comprehensive metabolomic and transcriptomic analyses suggested the disturbance of mTORC1-related signaling, including deteriorated energy status and suppressed mitochondrial oxidative function. In summary, we successfully established anin vitroskeletal muscle model of IOPD using patient-specific iPSCs. Disturbed mTORC1 signaling may contribute to the pathogenesis of skeletal muscle damage in IOPD, and may be a potential therapeutic target for Pompe disease.
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DOI：
10.1042/bj20111416
发表时间：
2012-02-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Roach PJ;Depaoli-Roach AA;Hurley TD;Tagliabracci VS
通讯作者：
Tagliabracci VS
重组人酸性α-葡萄糖苷酶：对婴儿发病的庞贝氏病的主要临床益处。
影响因子：
9.9
作者：
P. Kishnani;D. Corzo;M. Nicolino;B. Byrne;H. Mandel;W. Hwu;N. Leslie;J. Levine;C. Spencer;M. McDonald;J. Li;J. Dumontier;M. Halberthal;Y. Chien;R. Hopkin;S. Vijayaraghavan;D. Gruskin;D. Bartholomew;A. T. van der Ploeg;J. Clancy;R. Parini;G. Morin;M. Beck;G. de la Gastine;M. Jokic;B. Thurberg;S. Richards;D. Bali;M. Davison;M. Worden;Y. Chen;J. Wraith
通讯作者：
J. Wraith
DOI：
10.1007/bf02889851
发表时间：
1984-01-01
期刊：
VIRCHOWS ARCHIV B-CELL PATHOLOGY INCLUDING MOLECULAR PATHOLOGY
影响因子：
--
作者：
GRIFFIN, JL
通讯作者：
GRIFFIN, JL
DOI：
10.1152/ajpregu.00212.2014
发表时间：
2014-11-15
影响因子：
2.8
作者：
Shemesh, Adi;Wang, Yichen;Zong, Haihong
通讯作者：
Zong, Haihong
影响因子：
8
作者：
Shin, S.;Wolgamott, L.;Yoon, S-O
通讯作者：
Yoon, S-O