Preston Laura C, Lipscomb Simon, Robinson Paul, Mogensen Jens, McKenna William J, Watkins Hugh, Ashley Chris C, Redwood Charles S
Department of Physiology, University of Oxford, Oxford, UK.
Pflugers Arch. 2007 Mar;453(6):771-6. doi: 10.1007/s00424-006-0161-7. Epub 2006 Sep 26.
We recently reported a dilated cardiomyopathy (DCM) causing mutation in a novel disease gene, TNNC1, which encodes cardiac troponin C (TnC). We have determined how this mutation, Gly159Asp, affects contractile regulation when incorporated into muscle fibres. Endogenous troponin in rabbit skinned psoas fibres was partially replaced by recombinant human cardiac troponin containing either wild-type or Gly159Asp TnC. We measured both the force-pCa relationship of these fibres and the activation rate using the caged-Ca(2+) compound nitrophenyl-EGTA. Gly159Asp TnC had no significant effect on either the Ca(2+) sensitivity or cooperativity of force generation when compared to wild type. However, the mutation caused a highly significant (ca. 50%) decrease in the rate of activation. This study shows that whilst not affecting the force-pCa relationship, the mutation Gly159Asp causes a significant decrease in the rate of force production and a change in the relationship between the rate of force production and generated force. In vivo, this mutation may cause both a slowing of force generation and reduction in total systolic force. This represents a novel mechanism by which a cardiomyopathy-causing mutation can affect contractility.
我们最近报道了一种由新型疾病基因TNNC1突变引起的扩张型心肌病（DCM），该基因编码心肌肌钙蛋白C（TnC）。我们已经确定了这种Gly159Asp突变在整合到肌纤维中时如何影响收缩调节。兔去表皮腰大肌纤维中的内源性肌钙蛋白被含有野生型或Gly159Asp TnC的重组人心肌肌钙蛋白部分替代。我们使用笼形Ca(2+)化合物硝基苯-乙二醇双乙酸酯测量了这些纤维的力-pCa关系和激活速率。与野生型相比，Gly159Asp TnC对Ca(2+)敏感性或力产生的协同性均无显著影响。然而，该突变导致激活速率显著降低（约50%）。这项研究表明，虽然不影响力-pCa关系，但Gly159Asp突变会导致力产生速率显著降低，并改变力产生速率与产生的力之间的关系。在体内，这种突变可能导致力产生减慢和总收缩力降低。这代表了一种心肌病致病突变影响收缩性的新机制。
