Chang Alex Chia Yu, Ong Sang-Ging, LaGory Edward L, Kraft Peggy E, Giaccia Amato J, Wu Joseph C, Blau Helen M
Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305.
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):13120-13125. doi: 10.1073/pnas.1615340113. Epub 2016 Oct 31.
Duchenne muscular dystrophy (DMD) is an incurable X-linked genetic disease that is caused by a mutation in the dystrophin gene and affects one in every 3,600 boys. We previously showed that long telomeres protect mice from the lethal cardiac disease seen in humans with the same genetic defect, dystrophin deficiency. By generating the mdx/mTR mouse model with "humanized" telomere lengths, the devastating dilated cardiomyopathy phenotype seen in patients with DMD was recapitulated. Here, we analyze the degenerative sequelae that culminate in heart failure and death in this mouse model. We report progressive telomere shortening in developing mouse cardiomyocytes after postnatal week 1, a time when the cells are no longer dividing. This proliferation-independent telomere shortening is accompanied by an induction of a DNA damage response, evident by p53 activation and increased expression of its target gene p21 in isolated cardiomyocytes. The consequent repression of Pgc1α/β leads to impaired mitochondrial biogenesis, which, in conjunction with the high demands of contraction, leads to increased oxidative stress and decreased mitochondrial membrane potential. As a result, cardiomyocyte respiration and ATP output are severely compromised. Importantly, treatment with a mitochondrial-specific antioxidant before the onset of cardiac dysfunction rescues the metabolic defects. These findings provide evidence for a link between short telomere length and metabolic compromise in the etiology of dilated cardiomyopathy in DMD and identify a window of opportunity for preventive interventions.
杜兴氏肌肉营养不良症（DMD）是一种无法治愈的X连锁遗传病，由肌营养不良蛋白基因的突变引起，每3600名男孩中就有1人受其影响。我们之前表明，长端粒可保护小鼠免受与人类相同遗传缺陷（肌营养不良蛋白缺乏）相关的致命性心脏病的影响。通过构建具有“人源化”端粒长度的mdx/mTR小鼠模型，重现了DMD患者中出现的严重扩张型心肌病表型。在此，我们分析了在该小鼠模型中导致心力衰竭和死亡的退行性后遗症。我们报告，出生后第1周后，发育中的小鼠心肌细胞中端粒逐渐缩短，此时细胞不再分裂。这种与增殖无关的端粒缩短伴随着DNA损伤反应的诱导，在分离的心肌细胞中表现为p53激活及其靶基因p21表达增加。由此导致的Pgc1α/β抑制导致线粒体生物发生受损，这与收缩的高需求一起，导致氧化应激增加和线粒体膜电位降低。结果，心肌细胞呼吸和ATP输出严重受损。重要的是，在心脏功能障碍发作前用线粒体特异性抗氧化剂治疗可挽救代谢缺陷。这些发现为端粒长度缩短与DMD扩张型心肌病病因中的代谢受损之间的联系提供了证据，并确定了预防性干预的机会窗口。
