Metzger J M, Wahr P A, Michele D E, Albayya F, Westfall M V
Department of Physiology, School of Medicine, University of Michigan, Ann Arbor, MI, USA.
Circ Res. 1999 Jun 11;84(11):1310-7. doi: 10.1161/01.res.84.11.1310.
Cardiac myosin heavy chain (MHC) isoforms are known to play a key role in defining the dynamic contractile behavior of the heart during development. It remains unclear, however, whether cardiac MHC isoforms influence other important features of cardiac contractility, including the Ca2+ sensitivity of isometric tension development. To address this question, adult rats were treated chemically to induce the hypothyroid state and cause a transition in the ventricular cardiac MHC isoform expression pattern from predominantly the alpha-MHC isoform to exclusively the beta-MHC isoform. We found a significant desensitization in the Ca2+ sensitivity of tension development in beta-MHC-expressing ventricular myocytes (pCa50=5. 51+/-0.03, where pCa is -log[Ca2+], and pCa50 is pCa at which tension is one-half maximal) compared with that in predominantly alpha-MHC-expressing myocytes (pCa50=5.68+/-0.05). No differences between the 2 groups were observed in the steepness of the tension-pCa relationship or in the maximum isometric force generated. Instantaneous stiffness measurements were made that provide a relative measure of changes in the numbers of myosin crossbridges attached to actin during Ca2+ activation. Results showed that the relative stiffness-pCa relationship was shifted to the right in beta-MHC-expressing myocytes compared with the alpha-MHC-expressing cardiac myocytes (pCa50=5.47+/-0.05 versus 5.76+/-0.05, respectively). We conclude that MHC isoform switching in adult cardiac myocytes alters the Ca2+ sensitivity of stiffness and tension development. These results suggest that the activation properties of the thin filament are in part MHC isoform dependent in cardiac muscle, indicating an additional role for MHC isoforms in defining cardiac contractile function.
已知心肌肌球蛋白重链（MHC）异构体在心脏发育过程中确定心脏的动态收缩行为方面起着关键作用。然而，目前尚不清楚心脏MHC异构体是否会影响心脏收缩性的其他重要特征，包括等长张力发展的Ca2+敏感性。为了解决这个问题，对成年大鼠进行化学处理以诱导甲状腺功能减退状态，并使心室心脏MHC异构体表达模式从主要为α-MHC异构体转变为仅为β-MHC异构体。我们发现，与主要表达α-MHC的心肌细胞相比，表达β-MHC的心室肌细胞中张力发展的Ca2+敏感性显著降低（pCa50 = 5.51±0.03，其中pCa为-log[Ca2+]，pCa50是张力为最大张力一半时的pCa）（pCa50 = 5.68±0.05）。两组在张力-pCa关系的斜率或产生的最大等长力方面均未观察到差异。进行了瞬时刚度测量，该测量提供了Ca2+激活过程中附着于肌动蛋白的肌球蛋白横桥数量变化的相对测量值。结果表明，与表达α-MHC的心肌细胞相比，表达β-MHC的心肌细胞中相对刚度-pCa关系向右移动（pCa50分别为5.47±0.05和5.76±0.05）。我们得出结论，成年心肌细胞中的MHC异构体转换会改变刚度和张力发展的Ca2+敏感性。这些结果表明，细肌丝的激活特性在一定程度上取决于心肌中的MHC异构体，这表明MHC异构体在定义心脏收缩功能方面具有额外作用。
