R-92L and R-92W mutations in cardiac troponin T lead to distinct energetic phenotypes in intact mouse hearts
R-92L and R-92W mutations in cardiac troponin T lead to distinct energetic phenotypes in intact mouse hearts
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DOI：
10.1529/biophysj.107.107557
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发表时间：
2007-09-01
影响因子：
3.4
通讯作者：
Ingwall, Joanne S.
中科院分区：
文献类型：
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作者：
He, Huamei;Javadpour, Maryam M.;Ingwall, Joanne S.
现在已知肌钙蛋白T（TnT）尾部的柔性决定瘦。lamine构象，因此交叉桥循环性能，扩展经典的TnT的结构作用，以调节肌节功能的动态作用。在这里，使用转基因小鼠轴承R-92 W和R-92 L错义突变的心脏TnT已知改变的灵活性的TnT原肌球蛋白结合域，我们发现在整个心脏水平的收缩成本的突变特异性差异。与年龄和性别匹配的同胞心脏相比，突变心脏表现出更大的ATP利用率，使用P-31 NMR光谱测量，在所有工作负荷下[ATP]和[PCr]以及垂直条Delta G（类似于ATP）垂直条降低，在所有能量状态下严重收缩和舒张功能障碍。R-92 W心脏比R-92 L心脏表现出更严重的能量异常和更大的收缩功能障碍。当[Ca 2 +]用于增加突变心脏的工作时，增加收缩的成本异常高，但在β-肾上腺素能激动剂多巴酚丁胺的供应下恢复正常。这些结果表明，心脏TnT的TM结合结构域中的R-92 L和R-92 W突变改变薄。遗憾的是，结构和灵活性足以导致整个心脏能量和收缩性能的严重缺陷，并且这些变化的幅度是突变特异性的。
It is now known that the flexibility of the troponin T (TnT) tail determines thin. lament conformation and hence cross-bridge cycling properties, expanding the classic structural role of TnT to a dynamic role regulating sarcomere function. Here, using transgenic mice bearing R-92Wand R-92L missense mutations in cardiac TnT known to alter the flexibility of the TnT tropomyosin-binding domain, we found mutation-specific differences in the cost of contraction at the whole heart level. Compared to age- and gender-matched sibling hearts, mutant hearts demonstrate greater ATP utilization measured using P-31 NMR spectroscopy as decreases in [ATP] and [PCr] and vertical bar Delta G(similar to ATP)vertical bar at all workloads and profound systolic and diastolic dysfunction at all energetic states. R-92W hearts showed more severe energetic abnormalities and greater contractile dysfunction than R-92L hearts. The cost of increasing contraction was abnormally high when [Ca2+] was used to increase work in mutant hearts but was normalized with supply of the beta-adrenergic agonist dobutamine. These results show that R-92L and R-92W mutations in the TM-binding domain of cardiac TnT alter thin. lament structure and flexibility sufficiently to cause severe defects in both whole heart energetics and contractile performance, and that the magnitude of these changes is mutation specific.