The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms
The functional effect of dilated cardiomyopathy mutation (R144W) in mouse cardiac troponin T is differently affected by α- and β-myosin heavy chain isoforms
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DOI：
10.1152/ajpheart.00528.2014
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发表时间：
2015-04-15
影响因子：
4.8
通讯作者：
Chandra, Murali
中科院分区：
文献类型：
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作者：
Gollapudi, Sampath K.;Tardiff, Jil C.;Chandra, Murali
考虑到α-和β-肌球蛋白重链（MHC）亚型对肌钙蛋白T（TnT）如何调节收缩动力学的不同影响，我们假设扩张型心肌病（DCM）TnT突变的影响将被α-和β-MHC不同地改变。我们表征了正常（α-MHC）和转基因（β-MHC）小鼠心肌纤维与人DCM R141 W突变的小鼠TnT类似物（TnT（R144 W））重建的动态收缩特征。TnTR 144 W没有改变最大张力，但在α-和β-MHC纤维中以相似的程度减弱肌丝Ca 2+敏感性（pCa（50））。TnTR 144 W使α-MHC纤维中的跨桥（XB）畸变动力学（c）的速度衰减24%，使XB募集动力学（B）的速度衰减17%;然而，β-MHC纤维中的B和c均保持不变。同样，TnT（R144 W）仅在β-MHC纤维中减弱XB分离（g）和张力重建（k（tr））的速率。TnTR 144 W还仅在α-MHC纤维中将应变XB对新XB（γ）募集的影响降低了30%。由于c、B、g、k（tr）和γ受到基于细纤维的协同机制的强烈影响，我们得出结论，与TnT（R144 W）和α-MHC所引起的表型相比，TnT（R144 W）和β-MHC介导的细丝变化相互作用产生较不严重的功能表型。这些观察结果为携带TnT（R141 W）突变体的人类（β-MHC）与转基因小鼠研究相比死亡率较低提供了依据。我们的研究结果强烈表明，在将转基因小鼠研究的数据外推到人类心脏时，需要谨慎。
Given the differential impact of alpha-and beta-myosin heavy chain (MHC) isoforms on how troponin T (TnT) modulates contractile dynamics, we hypothesized that the effects of dilated cardiomyopathy (DCM) mutations in TnT would be altered differently by alpha-and beta-MHC. We characterized dynamic contractile features of normal (alpha-MHC) and transgenic (beta-MHC) mouse cardiac muscle fibers reconstituted with a mouse TnT analog (TnT(R144W)) of the human DCM R141W mutation. TnTR144W did not alter maximal tension but attenuated myofilament Ca2+ sensitivity (pCa(50)) to a similar extent in alpha-and beta-MHC fibers. TnTR144W attenuated the speed of cross-bridge (XB) distortion dynamics (c) by 24% and the speed of XB recruitment dynamics (b) by 17% in alpha-MHC fibers; however, both b and c remained unaltered in beta-MHC fibers. Likewise, TnT(R144W) attenuated the rates of XB detachment (g) and tension redevelopment (k(tr)) only in beta-MHC fibers. TnTR144W also decreased the impact of strained XBs on the recruitment of new XBs (gamma) by 30% only in alpha-MHC fibers. Because c, b, g, k(tr), and gamma are strongly influenced by thin filament-based cooperative mechanisms, we conclude that the TnT(R144W)-and beta-MHC-mediated changes in the thin filament interact to produce a less severe functional phenotype, compared with that brought about by TnT(R144W) and alpha-MHC. These observations provide a basis for lower mortality rates of humans (beta-MHC) harboring the TnT(R141W) mutant compared with transgenic mouse studies. Our findings strongly suggest that some caution is necessary when extrapolating data from transgenic mouse studies to human hearts.