Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Lab Invest. 2010 Apr;90(4):520-30. doi: 10.1038/labinvest.2010.43. Epub 2010 Feb 15.
Studies at the morphological and molecular level have found that transgenic (Tg) mice that overexpress myotrophin in the heart develop hypertrophy at the early age of 4 weeks; this condition worsens to heart failure (HF) at approximately 36 weeks. However, how the sustained effects of alteration in cytoarchitecture of the contractile machinery lead to malfunction of the normal heart remains unclear. Our data have shown that at 4 weeks, the cytoarchitecture observed in left ventricular (LV) tissue samples of Tg mice is similar to that of wild-type (WT) mice. However, as the disease progresses, cardiomyocytes show deterioration in some mitochondrial as well as myofibril features, evidenced by swelling of mitochondria, misalignment of myofibril structure, and blurring as well as breakage of Z-lines. At 36 weeks of age, Tg mice (the group in transition from hypertrophy to HF) show significant degenerative changes in cardiomyocytes, including swelling of mitochondria, disruption of the nuclear membrane, and absence of myofibril structure. Besides these, formation of myelin bodies was also observed, a feature typically found in human hearts with HF. Changes in Z-line architecture were further confirmed by alteration in the gene expression profile of desmin and tubulin, the two main cytoskeletal proteins. We thus conclude that Tg mice overexpressing myotrophin show no visible changes in the initiation phase (4 weeks); however, as the disease progresses, alterations in the cytoskeleton are found during the transition phase from hypertrophy to HF (36 weeks onward). Our data suggest that treatment for prevention/reversal of hypertrophy should start at the early stage of hypertrophy to prevent its transition to HF.
在形态学和分子水平的研究发现，在心脏中超表达肌生成素的转基因（Tg）小鼠在 4 周龄时就出现了肥大；这种情况在大约 36 周时恶化成心力衰竭（HF）。然而，持续改变收缩机制的细胞结构如何导致正常心脏功能障碍仍不清楚。我们的数据表明，在 4 周时，Tg 小鼠左心室（LV）组织样本中的细胞结构与野生型（WT）小鼠相似。然而，随着疾病的进展，心肌细胞显示出一些线粒体和肌原纤维特征的恶化，表现为线粒体肿胀、肌原纤维结构排列不齐以及 Z 线模糊和断裂。在 36 周龄时，从肥大向 HF 过渡的 Tg 小鼠（组）的心肌细胞出现明显的退行性变化，包括线粒体肿胀、核膜破裂以及肌原纤维结构缺失。除此之外，还观察到髓鞘体的形成，这是人类 HF 心脏中常见的特征。Z 线结构的变化进一步通过肌球蛋白和微管蛋白（两种主要的细胞骨架蛋白）的基因表达谱的改变得到证实。因此，我们得出结论，过表达肌生成素的 Tg 小鼠在起始阶段（4 周）没有出现明显变化；然而，随着疾病的进展，在从肥大向 HF 过渡的转换阶段发现了细胞骨架的改变（36 周及以后）。我们的数据表明，预防/逆转肥大的治疗应该在肥大的早期阶段开始，以防止其向 HF 转化。
