MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy
MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy
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DOI：
10.1371/journal.pone.0180064
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发表时间：
2017-06-28
期刊：
影响因子：
3.7
通讯作者：
dos Remedios, Cristobal G.
中科院分区：
文献类型：
--
作者：
McNamara, James W.;Li, Amy;dos Remedios, Cristobal G.
肌球蛋白的“超松弛状态”（SRX）代表心脏中运动的“储备”。SRX中的肌球蛋白头与粗丝结合，ATP酶速率非常低。SRX的变化可能调节心脏收缩力。我们以前证明，SRX是显着减少小鼠心肌细胞缺乏心肌肌球蛋白结合蛋白C（cMyBP-C）。在这里，我们报告的cMyBP-C基因（MYBPC 3）的突变的影响，使用样本从人类患者的肥厚型心肌病（HCM）。左心室（LV）样本从11 HCM患者获得后肌切除术，以减轻左心室流出道梗阻。将HCM样本基因分型为MYBPC 3突变阳性（MYBPC 3（mut））或阴性（HCMsmn），并与8个非衰竭供体心脏进行比较。与供体相比，只有MYBPC 3 mut样品显示出显著减少的SRX，其特征在于SRX中肌球蛋白头的数量和ATP周转的寿命都减少。在HCMsmn样品中未观察到这些变化。cMyBP-C的表达与SRX状态下肌球蛋白头的比例呈正相关（p < 0.01），表明cMyBP-C调节和维持SRX。与其他组相比，MYBPC 3 mut样品中肌球蛋白调节轻链的磷酸化显著降低，表明了补偿减少的SRX的潜在机制。我们的结论是，通过改变收缩力和肌节能量需求，减少SRX可能是MYBPC 3突变患者的一个重要疾病机制。
The "super-relaxed state" (SRX) of myosin represents a 'reserve' of motors in the heart. Myosin heads in the SRX are bound to the thick filament and have a very low ATPase rate. Changes in the SRX are likely to modulate cardiac contractility. We previously demonstrated that the SRX is significantly reduced in mouse cardiomyocytes lacking cardiac myosin binding protein C (cMyBP-C). Here, we report the effect of mutations in the cMyBP-C gene (MYBPC3) using samples from human patients with hypertrophic cardiomyopathy (HCM). Left ventricular (LV) samples from 11 HCM patients were obtained following myectomy surgery to relieve LV outflow tract obstruction. HCM samples were genotyped as either MYBPC3 mutation positive (MYBPC3(mut)) or negative (HCMsmn) and were compared to eight non-failing donor hearts. Compared to donors, only MYBPC3mut samples display a significantly diminished SRX, characterised by a decrease in both the number of myosin heads in the SRX and the lifetime of ATP turnover. These changes were not observed in HCMsmn samples. There was a positive correlation (p < 0.01) between the expression of cMyBP-C and the proportion of myosin heads in the SRX state, suggesting cMyBP-C modulates and maintains the SRX. Phosphorylation of the myosin regulatory light chain in MYBPC3mut samples was significantly decreased compared to the other groups, suggesting a potential mechanism to compensate for the diminished SRX. We conclude that by altering both contractility and sarcomeric energy requirements, a reduced SRX may be an important disease mechanism in patients with MYBPC3 mutations.