Increase in tension-dependent ATP consumption induced by cardiac troponin T mutation
Increase in tension-dependent ATP consumption induced by cardiac troponin T mutation
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DOI：
10.1152/ajpheart.00571.2005
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发表时间：
2005-11-01
影响因子：
4.8
通讯作者：
Tardiff, JC
中科院分区：
文献类型：
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作者：
Chandra, M;Tschirgi, ML;Tardiff, JC
在家族性肥厚型心肌病(FHC)中，心肌肌钙蛋白T(CTnT)的不同突变如何导致不同的下游细胞重构仍不清楚。为了探索cTnT不同突变对心肌细胞不同影响的分子基础，我们研究了表达野生型cTnT(WTTG)、R92W cTnT、R92L cTnT和Delta-160 cTnT(氨基酸160缺失)的不同转基因(TG)小鼠心脏的洗涤剂皮肤肌纤维束的机械活性。突变型cTnT在R92W和R92L Tg小鼠心脏中的含量与心肌细胞cTnT总量的50%相似，在Delta-160Tg小鼠心脏中的含量与35%相似。在所有突变的cTnT TG心肌纤维中，肌丝对钙的敏感性均增强。与WTTG纤维相比，在短肌节长度(SL)为1.9µm(P<；0.001)时，R92WTG纤维的钙敏感性增加了2.2倍，R92L纤维增加了2.0倍，Delta-160纤维增加了1.3倍。在长SL为2.3微米时，钙敏感性显著增加(P<；0.01)(R92W，2.5倍；R92L，1.9倍；Delta-160，1.3倍)。Ca~(2+)激活的最大张力在所有TG肌纤维中保持不变。然而，Delta-160TG肌纤维在短SL(23%，P<；0.005)和长SL(37%，P<；0.0001)时的张力依赖性三磷酸腺苷消耗显著增加，这表明突变导致跨桥分离速率常数的变化。慢性应激对心肌细胞内相对细胞ATP水平的影响可能导致能量依赖性钙稳态机制的紧张。这可能导致了我们在Delta-160TG心肌细胞中观察到的病理性重构，其中肌浆网(Endo)钙-ATPase 2/磷蛋白的比率显著降低。我们的结果表明，施加在心肌细胞上的不同类型的压力会触发不同的细胞信号，从而导致可能是某些突变所特有的重塑。
How different mutations in cardiac troponin T (cTnT) lead to distinct secondary downstream cellular remodeling in familial hypertrophic cardiomyopathy (FHC) remains elusive. To explore the molecular basis for the distinct impact of different mutations in cTnT on cardiac myocytes, we studied mechanical activity of detergent-skinned muscle fiber bundles from different lines of transgenic (TG) mouse hearts that express wild-type cTnT (WTTG), R92W cTnT, R92L cTnT, and Delta-160 cTnT (deletion of amino acid 160). The amount of mutant cTnT is similar to 50% of the total myocellular cTnT in both R92W and R92L TG mouse hearts and similar to 35% in Delta-160 TG mouse hearts. Myofilament Ca2+ sensitivity was enhanced in all mutant cTnT TG cardiac muscle fibers. Compared with the WTTG fibers, Ca2+ sensitivity increased significantly at short sarcomere length (SL) of 1.9 mu m (P < 0.001) in R92W TG fibers by 2.2-fold, in R92L by 2.0-fold, and in Delta-160 by 1.3-fold. At long SL of 2.3 mu m, Ca2+ sensitivity increased significantly (P < 0.01) in a similar manner (R92W, 2.5-fold; R92L, 1.9-fold; Delta- 160, 1.3- fold). Ca2+-activated maximal tension remained unaltered in all TG muscle fibers. However, tension-dependent ATP consumption increased significantly in Delta-160 TG muscle fibers at both short SL (23%, P < 0.005) and long SL (37%, P < 0.0001), suggesting a mutation-induced change in cross-bridge detachment rate constant. Chronic stresses on relative cellular ATP level in cardiac myocytes may cause a strain on energy-dependent Ca2+ homeostatic mechanisms. This may result in pathological remodeling that we observed in Delta- 160 TG cardiac myocytes where the ratio of sarco(endo) plasmic reticulum Ca2+-ATPase 2/phospholamban decreased significantly. Our results suggest that different types of stresses imposed on cardiac myocytes would trigger distinct cellular signaling, which leads to remodeling that may be unique to some mutants.