Hayes James B, Burnette Dylan T
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine Basic Sciences, Nashville, Tennessee, USA.
Cytoskeleton (Hoboken). 2025 Feb 17. doi: 10.1002/cm.22006.
Sarcomeres are the fundamental contractile units of striated muscle. The functional roles of the cardiac-specific myosin heavy chains, MYH6 (α myosin II) and MYH7 (β myosin II) during sarcomere assembly remain controversial. To address this, we utilized a selective MYH7 inhibitor, mavacamten, in combination with siRNA-mediated knockdown of MYH6 or MYH7 in human induced pluripotent stem cell-derived cardiomyocytes (hiCMs). Our results demonstrate that sarcomere assembly proceeds when either MYH6 or MYH7 is independently depleted, suggesting functional redundancy. However, pharmacological inhibition of MYH7 contractility by mavacamten disrupts sarcomere assembly in a concentration-dependent manner. Sensitivity to mavacamten correlated with the relative abundance of MYH6 and MYH7: sarcomere assembly by MYH7-enriched (i.e., MYH6-depleted) hiCMs was more sensitive to mavacamten (IC = 0.1 μM), while assembly by MYH6-enriched (i.e., MYH7-depleted) hiCMs was less sensitive (IC = 0.5 μM). These findings suggest that MYH7-mediated contractility is required for sarcomere assembly, but only when MYH7 is present within a cardiac myocyte. We conclude that the MYH7/MYH6 ratio impacts the susceptibility of sarcomere assembly to pharmacological inhibition.
肌节是横纹肌的基本收缩单位。心脏特异性肌球蛋白重链MYH6（α肌球蛋白II）和MYH7（β肌球蛋白II）在肌节组装过程中的功能作用仍存在争议。为了解决这个问题，我们在人诱导多能干细胞衍生的心肌细胞（hiCMs）中使用了选择性MYH7抑制剂mavacamten，并结合siRNA介导的MYH6或MYH7敲低。我们的结果表明，当MYH6或MYH7单独缺失时，肌节组装仍能进行，这表明存在功能冗余。然而，mavacamten对MYH7收缩性的药理抑制以浓度依赖的方式破坏肌节组装。对mavacamten的敏感性与MYH6和MYH7的相对丰度相关：富含MYH7（即MYH6缺失）的hiCMs进行的肌节组装对mavacamten更敏感（IC = 0.1 μM），而富含MYH6（即MYH7缺失）的hiCMs进行的组装则不太敏感（IC = 0.5 μM）。这些发现表明，肌节组装需要MYH7介导的收缩性，但仅当MYH7存在于心肌细胞中时才需要。我们得出结论，MYH7/MYH6比值会影响肌节组装对药理抑制的敏感性。
