Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.
Increased tissue stiffness triggers contractile dysfunction and telomere shortening in dystrophic cardiomyocytes.
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增加的组织硬度触发收缩功能障碍和端粒缩短在营养不良的心肌细胞。
DOI：
10.1016/j.stemcr.2021.04.018
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发表时间：
2021-09-14
影响因子：
5.9
通讯作者：
Blau HM
中科院分区：
文献类型：
--
作者：
Chang ACY;Pardon G;Chang ACH;Wu H;Ong SG;Eguchi A;Ancel S;Holbrook C;Ramunas J;Ribeiro AJS;LaGory EL;Wang H;Koleckar K;Giaccia A;Mack DL;Childers MK;Denning C;Day JW;Wu JC;Pruitt BL;Blau HM
杜氏肌营养不良症（DMD）是一种罕见的X连锁隐性疾病，与严重的进行性肌肉变性有关，最终因心肺功能衰竭而死亡。我们以前观察到一个意想不到的增殖无关的端粒缩短的心肌细胞的DMD小鼠模型。在这里，我们使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）提供机制见解。使用牵引力显微镜，我们发现DMD hiPSC-CM在纤维化样生物工程水凝胶上表现出力生成缺陷，异常钙处理和活性氧水平增加。此外，我们观察到DMD hiPSC-CM中有丝分裂后端粒缩短与shelterin复合物、端粒加帽蛋白和p53 DNA损伤反应的激活的下调一致。这种端粒缩短被抑制DMD心肌细胞收缩的blebistatin阻断。我们的研究强调了纤维硬化在DMD心肌病病因中的作用。此外，我们的数据表明，端粒缩短是渐进的，收缩依赖性，机械敏感性，并建议治疗干预点。DMD hiPSC-CM表现出异常的钙处理和有缺陷的力生成DMD hiPSC-CM经历增殖非依赖性端粒缩短端粒缩短激活p53 DNA损伤途径DMD hiPSC-CM中的端粒缩短是收缩依赖性的在这篇文章中，Chang，Blau及其同事表明杜氏肌营养不良症（DMD）iPSC衍生的心肌细胞表现出增殖非依赖性端粒缩短，p53激活和线粒体功能障碍。
Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disease that is associated with severe progressive muscle degeneration culminating in death due to cardiorespiratory failure. We previously observed an unexpected proliferation-independent telomere shortening in cardiomyocytes of a DMD mouse model. Here, we provide mechanistic insights using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Using traction force microscopy, we show that DMD hiPSC-CMs exhibit deficits in force generation on fibrotic-like bioengineered hydrogels, aberrant calcium handling, and increased reactive oxygen species levels. Furthermore, we observed a progressive post-mitotic telomere shortening in DMD hiPSC-CMs coincident with downregulation of shelterin complex, telomere capping proteins, and activation of the p53 DNA damage response. This telomere shortening is blocked by blebbistatin, which inhibits contraction in DMD cardiomyocytes. Our studies underscore the role of fibrotic stiffening in the etiology of DMD cardiomyopathy. In addition, our data indicate that telomere shortening is progressive, contraction dependent, and mechanosensitive, and suggest points of therapeutic intervention. DMD hiPSC-CMs exhibit aberrant calcium handling and defective force generation DMD hiPSC-CMs undergo proliferation-independent telomere shortening Telomere shortening activates the p53 DNA damage pathway Telomere shortening in DMD hiPSC-CMs is contraction dependent In this article, Chang, Blau, and colleagues show that Duchenne muscular dystrophy (DMD) iPSC-derived cardiomyocytes exhibit proliferation-independent telomere shortening, p53 activation and mitochondrial dysfunction.
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影响因子：
37.8
作者：
McNally EM;Kaltman JR;Benson DW;Canter CE;Cripe LH;Duan D;Finder JD;Groh WJ;Hoffman EP;Judge DP;Kertesz N;Kinnett K;Kirsch R;Metzger JM;Pearson GD;Rafael-Fortney JA;Raman SV;Spurney CF;Targum SL;Wagner KR;Markham LW;Working Group of the National Heart, Lung, and Blood Institute;Parent Project Muscular Dystrophy
通讯作者：
Parent Project Muscular Dystrophy
影响因子：
16.8
作者：
Arnoult N;Karlseder J
通讯作者：
Karlseder J
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF
影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
--
作者：
Burridge PW;Holmström A;Wu JC
通讯作者：
Wu JC