Challenging Current Paradigms Related to Cardiomyopathies ARE CHANGES IN THE Ca2+ SENSITIVITY OF MYOFILAMENTS CONTAINING CARDIAC TROPONIN C MUTATIONS (G159D AND L29Q) GOOD PREDICTORS OF THE PHENOTYPIC OUTCOMES?
Challenging Current Paradigms Related to Cardiomyopathies ARE CHANGES IN THE Ca2+ SENSITIVITY OF MYOFILAMENTS CONTAINING CARDIAC TROPONIN C MUTATIONS (G159D AND L29Q) GOOD PREDICTORS OF THE PHENOTYPIC OUTCOMES?
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DOI：
10.1074/jbc.m804070200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Potter, James D.
中科院分区：
文献类型：
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作者：
Dweck, David;Hus, Nir;Potter, James D.
心肌肌钙蛋白 C (CTnC) 中的两个新突变（G159D 和 L29Q）分别将其表型结果与扩张型心肌病 (DCM) 和肥厚型心肌病 (HCM) 相关。目前的范式提出，与 DCM 相关的肌节突变会降低肌丝 Ca2+ 敏感性，而与 HCM 相关的肌节突变会增加肌丝 Ca2+ 敏感性。因此，我们将突变的 CTnC 纳入带皮心肌中，以确定它们对张力和 ATP 酶活性的 Ca2+ 敏感性的影响是否与当前的范例和表型结果一致。当掺入受调节的肌动球蛋白丝中时，G159D-CTnC 会降低张力和 ATP 酶激活的 Ca2+ 敏感性，并降低最大 ATP 酶活性。在相同条件下，L29Q-CTnC没有效果。令人惊讶的是，通过纤维张力测量的表观 G159D-CTnC Ca2+ 亲和力的变化在分离的 CTnC 中没有发生，并且在分离的 L29Q-CTnC 中测量的大变化在纤维中也没有表现出来。这些违反直觉的发现通过心肌肌钙蛋白水平及更高水平发生的 Ca2+ 亲和力转变得到证实，这意味着随着肌丝层次水平的增加，这些突变的真正影响变得明显。因此，代表大型协作机器的收缩装置可以提供收缩 Ca2+ 调节变化（G159D）或不变化（L29Q）的潜力。根据临床结果和当前的范例，G159D-CTnC 的肌丝脱敏预计会削弱心肌的收缩力，而 L29Q-CTnC 的肌丝变化缺乏可能会保留舒张和收缩功能。
Two novel mutations (G159D and L29Q) in cardiac troponin C (CTnC) associate their phenotypic outcomes with dilated (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Current paradigms propose that sarcomeric mutations associated with DCM decrease the myofilament Ca2+ sensitivity, whereas those associated with HCM increase it. Therefore, we incorporated the mutant CTnCs into skinned cardiac muscle in order to determine if their effects on the Ca2+ sensitivities of tension and ATPase activity coincide with the current paradigms and phenotypic outcomes. The G159D-CTnC decreases the Ca2+ sensitivity of tension and ATPase activation and reduces the maximal ATPase activity when incorporated into regulated actomyosin filaments. Under the same conditions, the L29Q-CTnC has no effect. Surprisingly, changes in the apparent G159D-CTnC Ca2+ affinity measured by tension in fibers do not occur in the isolated CTnC, and large changes measured in the isolated L29Q-CTnC do not manifest in the fiber. These counterintuitive findings are justified through a transition in Ca2+ affinity occurring at the level of cardiac troponin and higher, implying that the true effects of these mutations become apparent as the hierarchical level of the myofilament increases. Therefore, the contractile apparatus, representing a large cooperative machine, can provide the potential for a change ( G159D) or no change ( L29Q) in the Ca2+ regulation of contraction. In accordance with the clinical outcomes and current paradigms, the desensitization of myofilaments from G159D-CTnC is expected to weaken the contractile force of the myocardium, whereas the lack of myofilament changes from L29Q-CTnC may preserve diastolic and systolic function.