Cardiomyopathy-Related Mutations in Cardiac Troponin C, L29Q and G159D, Have Divergent Effects on Rat Cardiac Myofiber Contractile Dynamics.
Cardiomyopathy-Related Mutations in Cardiac Troponin C, L29Q and G159D, Have Divergent Effects on Rat Cardiac Myofiber Contractile Dynamics.
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DOI：
10.1155/2012/824068
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发表时间：
2012
影响因子：
3
通讯作者：
Chandra M
中科院分区：
文献类型：
--
作者：
Gollapudi SK;Chandra M
以前对心肌病相关的心肌肌钙蛋白C(CTNC)突变的研究--L29Q和G159D--显示了不同的结果。由于缺乏对收缩动力学的研究，这种突变效应和它们对心脏表型的不同影响之间的联系仍然难以捉摸。我们假设，cTNC突变引起的细丝改变将影响整体肌丝的力学动力学，因为细丝动力学与钙结合和交叉桥(XB)循环动力学都存在相互作用。我们测量了重组野生型大鼠cTNC(CTnCWT)、cTnCL29Q和cTnCG159D突变体重组的清洁剂皮肤大鼠心肌乳头肌纤维的PCA-张力关系和收缩动力学。CTnCL29Q纤维表现出明显的钙敏感性降低，而cTnCG159D纤维则没有。两种突变体对钙激活的最大张力均无影响。在cTnCL29Q(26%)和cTnCG159D(25%)纤维中，XB募集动力学的比率增加。CTnCG159D纤维的XB变形动力学变化率增加(15%)。因此，cTnCL29Q突变体通过影响调节单位(原肌球蛋白-肌钙蛋白)的开/关动力学来调节XB的非循环池和循环池之间的平衡；而cTnCG159D突变体则增加了XB的循环率。CTnCL29Q和cTnCG159D对收缩动力学的不同影响可能为cTnCL29Q和cTnCG159D对心脏表型的不同影响提供线索。
Previous studies of cardiomyopathy-related mutations in cardiac troponin C (cTnC)—L29Q and G159D—have shown diverse findings. The link between such mutant effects and their divergent impact on cardiac phenotypes has remained elusive due to lack of studies on contractile dynamics. We hypothesized that a cTnC mutant-induced change in the thin filament will affect global myofilament mechanodynamics because of the interactions of thin filament kinetics with both Ca2+ binding and crossbridge (XB) cycling kinetics. We measured pCa-tension relationship and contractile dynamics in detergent-skinned rat cardiac papillary muscle fibers reconstituted with the recombinant wild-type rat cTnC (cTnCWT), cTnCL29Q, and cTnCG159D mutants. cTnCL29Q fibers demonstrated a significant decrease in Ca2+ sensitivity, but cTnCG159D fibers did not. Both mutants had no effect on Ca2+-activated maximal tension. The rate of XB recruitment dynamics increased in cTnCL29Q (26%) and cTnCG159D (25%) fibers. The rate of XB distortion dynamics increased in cTnCG159D fibers (15%). Thus, the cTnCL29Q mutant modulates the equilibrium between the non-cycling and cycling pool of XB by affecting the on/off kinetics of the regulatory units (Tropomyosin-Troponin); whereas, the cTnCG159D mutant increases XB cycling rate. Different effects on contractile dynamics may offer clue regarding how cTnCL29Q and cTnCG159D cause divergent effects on cardiac phenotypes.