Computational simulation of hypertrophic cardiomyopathy mutations in Troponin I:: Influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i
Computational simulation of hypertrophic cardiomyopathy mutations in Troponin I:: Influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i
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DOI：
10.1016/j.jbiomech.2006.09.026
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发表时间：
2007-01-01
影响因子：
2.4
通讯作者：
Chase, P. Bryant
中科院分区：
文献类型：
--
作者：
Kataoka, Aya;Hemmer, Carolyn;Chase, P. Bryant
家族性肥厚型心肌病 (FHQ 是一种遗传性疾病，其特征是心室肥厚、心律失常和过早猝死的风险增加。FHC 是由许多肌节蛋白基因的常染色体显性突变引起的；心脏细丝 Ca2+ 调节蛋白的许多突变与肌丝功能的 Ca2+ 敏感性增加有关。使用计算模拟来研究这些突变可能影响心肌肥厚的可能性。我们使用了心肌肌钙蛋白 I 特定突变的现有实验数据，这些突变在生理和生物物理测定中表现出增加的 Ca2+ 敏感性。模拟的 Ca2+ 瞬变被用作具有肌丝顺应性的三维半肌节生物力学模型，以预测产生的力。 Ca2+ 进入细胞质，-它们也会延长 Ca2+ 的去除时间，但对舒张期 Ca2+ 的影响很小。生物力学模型结果表明，尽管峰值 [Ca2+](i) 减少，但这些 cTnI 突变体会增加峰值力，但张力成本没有变化（每单位时间积分张力水解的 ATP）。 [Ca2+](i)，增加应力/应变，和/或增加 ATP 通量 (C) 2006 Elsevier Ltd. 保留所有权利。
Familial hypertrophic cardiomyopathy (FHQ is an inherited disease that is characterized by ventricular hypertrophy, cardiac arrhythmias and increased risk of premature sudden death. FHC is caused by autosomal-dominant mutations in genes for a number of sarcomeric proteins; many mutations in Ca2+-regulatory proteins of the cardiac thin filament are associated with increased Ca2+ sensitivity of myofilament function. Computational simulations were used to investigate the possibility that these mutations could affect the Ca2+ transient and mechanical response of a myocyte during a single cardiac cycle. We used existing experimental data for specific mutations of cardiac troponin I that exhibit increased Ca2+ sensitivity in physiological and biophysical assays. The simulated Ca2+ transients were used as input for a three-dimensional half-sarcomere biomechanical model with filament compliance to predict the resulting force. Mutations with the highest Ca2+ affinity (lowest K-m) values, exhibit the largest decrease in peak Ca2+ assuming a constant influx of Ca2+ into the cytoplasm,- they also prolong Ca2+ removal but have little effect on diastolic Ca2+. Biomechanical model results suggest that these cTnI mutants would increase peak force despite the decrease in peak [Ca2+](i). There is a corresponding increase in net ATP hydrolysis, with no change in tension cost (ATP hydrolyzed per unit of time-integrated tension). These simulations suggest that myofilament-initiated hypertrophic signaling could be associated with decreased [Ca2+](i), increased stress/strain, and/or increased ATP flux. (C) 2006 Elsevier Ltd. All rights reserved.