Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle.
Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle.
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Danicamtiv 增加肌球蛋白募集并改变心肌中的化学机械跨桥循环。
DOI：
10.1101/2023.01.31.526380
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发表时间：
2023
期刊：
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作者：
Kooiker,KristinaB;Mohran,Saffie;Turner,KyrahL;Ma,Weikang;Flint,Galina;Qi,Lin;Gao,Chengqian;Zheng,Yahan;McMillen,TimothyS;Mandrycky,Christian;Martinson,Amy;Mahoney-Schaefer,Max;Freeman,JeremyC;CostalesArenas,ElijahGabriela;
背景调节肌球蛋白功能是心肌病患者的一种新的治疗方法。Danicamtiv是一种新型肌球蛋白激活剂，目前正在进行临床试验，具有良好的临床前数据。虽然它是已知的，danicamtiv增加力和心肌细胞的收缩性，而不影响钙水平，详细的机制研究，其作用模式是lacking.METHODSPermeabilized猪心脏组织和肌原纤维被用于X-射线衍射和机械测量。使用遗传性扩张型心肌病小鼠模型来评估丹尼卡替夫纠正收缩缺陷的能力。结果丹尼卡替夫通过增加处于ON状态的肌球蛋白数量和减缓跨桥转换来增加力和钙敏感性。我们的详细分析表明，抑制ADP释放的结果在降低跨桥营业额与跨桥停留附着时间更长，延长肌原纤维松弛。Danicamtiv纠正了去膜组织中钙敏感性降低，完整心脏组织中异常抽搐幅度和动力学，以及整个器官中射血分数降低。结论Danicamtiv的详细研究表明，增加肌球蛋白募集和改变跨桥循环是增加心肌力和钙敏感性的2种机制。肌球蛋白激活剂如Danicamtiv可以治疗遗传性扩张型心肌病的收缩功能减退表型。
BACKGROUNDModulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known that danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking.METHODSPermeabilized porcine cardiac tissue and myofibrils were used for X-ray diffraction and mechanical measurements. A mouse model of genetic dilated cardiomyopathy was used to evaluate the ability of danicamtiv to correct the contractile deficit.RESULTSDanicamtiv increased force and calcium sensitivity via increasing the number of myosins in the ON state and slowing cross-bridge turnover. Our detailed analysis showed that inhibition of ADP release results in decreased cross-bridge turnover with cross bridges staying attached longer and prolonging myofibril relaxation. Danicamtiv corrected decreased calcium sensitivity in demembranated tissue, abnormal twitch magnitude and kinetics in intact cardiac tissue, and reduced ejection fraction in the whole organ.CONCLUSIONSAs demonstrated by the detailed studies of Danicamtiv, increasing myosin recruitment and altering cross-bridge cycling are 2 mechanisms to increase force and calcium sensitivity in cardiac muscle. Myosin activators such as Danicamtiv can treat the causative hypocontractile phenotype in genetic dilated cardiomyopathy.