Groen Marcel, López-Dávila Alfredo Jesus, Zittrich Stefan, Pfitzer Gabriele, Stehle Robert
Department of Neurology and Neurogeriatry, Johannes Wesling Medical Center, Ruhr-University Bochum, Bochum, Germany.
Department of Molecular and Cell Physiology, Hannover Medical School, Hanover, Germany.
Front Physiol. 2020 Jun 3;11:516. doi: 10.3389/fphys.2020.00516. eCollection 2020.
Length-dependent activation of calcium-dependent myocardial force generation provides the basis for the Frank-Starling mechanism. To directly compare the effects of mutations associated with hypertrophic cardiomyopathy and dilated cardiomyopathy, the native troponin complex in skinned trabecular fibers of guinea pigs was exchanged with recombinant heterotrimeric, human, cardiac troponin complexes containing different human cardiac troponin T subunits (hcTnT): hypertrophic cardiomyopathy-associated hcTnT, dilated cardiomyopathy-associated hcTnT or the wild type hcTnT (hcTnT) serving as control. Force-calcium relations of exchanged fibers were explored at short fiber length defined as 110% of slack length ( ) and long fiber length defined as 125% of (1.25 ). At short fiber length (1.1 ), calcium sensitivity of force generation expressed by -log [Ca] required for half-maximum force generation (pCa) was highest for the hypertrophic cardiomyopathy-associated mutation R130C (5.657 ± 0.019), intermediate for the wild type control (5.580 ± 0.028) and lowest for the dilated cardiomyopathy-associated mutation ΔK210 (5.325 ± 0.038). Lengthening fibers from 1.1 to 1.25 increased calcium sensitivity in fibers containing hcTnT (delta-pCa = +0.030 ± 0.010), did not alter calcium sensitivity in the wild type control (delta-pCa = -0.001 ± 0.010), and decreased calcium sensitivity in fibers containing hcTnT (delta-pCa = -0.034 ± 0.013). Length-dependent activation indicated by the delta-pCa was highly significantly ( < 0.001) different between the two mutations. We hypothesize that primary effects of mutations on length-dependent activation contribute to the development of the diverging phenotypes in hypertrophic and dilated cardiomyopathy.
钙依赖性心肌力产生的长度依赖性激活为Frank-Starling机制提供了基础。为了直接比较与肥厚型心肌病和扩张型心肌病相关的突变的影响，将豚鼠皮肤小梁纤维中的天然肌钙蛋白复合物与含有不同人类心脏肌钙蛋白T亚基（hcTnT）的重组异源三聚体人类心脏肌钙蛋白复合物进行交换：与肥厚型心肌病相关的hcTnT、与扩张型心肌病相关的hcTnT或作为对照的野生型hcTnT（hcTnT）。在定义为松弛长度（ ）的110%的短纤维长度和定义为 （1.25 ）的125%的长纤维长度下，研究交换纤维的力-钙关系。在短纤维长度（1.1 ）时，产生最大力的一半所需的力产生的钙敏感性由-log [Ca]表示（pCa），对于与肥厚型心肌病相关的突变R¹³⁰C最高（5.657 ± 0.019），对于野生型对照为中等（5.580 ± 0.028），对于与扩张型心肌病相关的突变ΔK²¹⁰最低（5.325 ± 0.038）。将纤维长度从1.1 延长至1.25 可增加含有hcTnT的纤维中的钙敏感性（δ-pCa = +0.030 ± 0.010），在野生型对照中不改变钙敏感性（δ-pCa = -0.001 ± 0.010），并降低含有hcTnT的纤维中的钙敏感性（δ-pCa = -0.034 ± 0.013）。两个突变之间由δ-pCa表示的长度依赖性激活高度显著不同（ < 0.001）。我们假设突变对长度依赖性激活的主要影响有助于肥厚型和扩张型心肌病中不同表型的发展。
