Hypertrophic cardiomyopathy-related β-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells
Hypertrophic cardiomyopathy-related β-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells
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DOI：
10.1152/ajpheart.00686.2004
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发表时间：
2005-03-01
影响因子：
4.8
通讯作者：
Kraft, T
中科院分区：
文献类型：
--
作者：
Kirschner, SE;Becker, E;Kraft, T
肥厚型心肌病相关的β-肌球蛋白突变引起高度可变的钙敏感性，并伴有个体肌细胞之间的功能失衡。美国生理学杂志心脏循环生理学288：H1242-H1251，2005年。首次发表于2004年11月18日; doi：10.1152/ajpheart.00686.2004。心肌肌球蛋白重链（β-MHC）的致病突变在大约三分之一的肥厚型心肌病（HCM）家族中被发现。然而，肌球蛋白突变对肌丝钙敏感性的影响在很大程度上是未知的。由于正常和突变的心脏MHC也表达于慢收缩骨骼肌，这是更容易接近和较少的适应性反应，在心肌中看到，我们比较了钙敏感性（pCa（50））和陡峭的力pCa关系（协同性）的单一比目鱼肌纤维从健康个体和HCM患者的三个家庭与选定的肌球蛋白突变。Arg 723 Gly和Arg 719 Trp突变的纤维显示平均pCa（50）降低，而Ile 736 Thr突变的纤维显示平均pCa（50）略微增加，在低钙浓度下具有较高的活性力，即使在松弛条件下也具有残余活性力。此外，携带相同突变的个体纤维之间的pCa（50）存在显著的变异性，范围从几乎正常的反应到在对照中未观察到的高度显著差异。虽然平均pCa（50）的变化可能表明特定的药物治疗（例如，例如，在一个实施例中，钙拮抗剂），观察到的个体肌细胞之间的大的功能变异性可能否定这种选择性治疗。更重要的是，不同纤维之间pCa（50）的变化可能导致力产生的不平衡，是心肌收缩功能障碍和紊乱发展的主要原因。
Hypertrophic cardiomyopathy- related beta-myosin mutations cause highly variable calcium sensitivity with functional imbalances among individual muscle cells. Am J Physiol Heart Circ Physiol 288: H1242-H1251, 2005. First published November 18, 2004; doi:10.1152/ajpheart.00686.2004.-Disease-causing mutations in cardiac myosin heavy chain (beta-MHC) are identified in about one-third of families with hypertrophic cardiomyopathy (HCM). The effect of myosin mutations on calcium sensitivity of the myofilaments, however, is largely unknown. Because normal and mutant cardiac MHC are also expressed in slow-twitch skeletal muscle, which is more easily accessible and less subject to the adaptive responses seen in myocardium, we compared the calcium sensitivity (pCa(50)) and the steepness of force-pCa relations (cooperativity) of single soleus muscle fibers from healthy individuals and from HCM patients of three families with selected myosin mutations. Fibers with the Arg723Gly and Arg719Trp mutations showed a decrease in mean pCa(50), whereas those with the Ile736Thr mutation showed slightly increased mean pCa(50) with higher active forces at low calcium concentrations and residual active force even under relaxing conditions. In addition, there was a marked variability in pCa(50) between individual fibers carrying the same mutation ranging from an almost normal response to highly significant differences that were not observed in controls. While changes in mean pCa(50) may suggest specific pharmacological treatment ( e. g., calcium antagonists), the observed large functional variability among individual muscle cells might negate such selective treatment. More importantly, the variability in pCa(50) from fiber to fiber is likely to cause imbalances in force generation and be the primary cause for contractile dysfunction and development of disarray in the myocardium.