Cardiac MyBP-C phosphorylation regulates the Frank-Starling relationship in murine hearts.
Cardiac MyBP-C phosphorylation regulates the Frank-Starling relationship in murine hearts.
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DOI：
10.1085/jgp.202012770
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发表时间：
2021-07-05
期刊：
影响因子：
--
通讯作者：
McDonald KS
中科院分区：
文献类型：
--
作者：
Hanft LM;Fitzsimons DP;Hacker TA;Moss RL;McDonald KS
心肌肌球蛋白结合蛋白C（cMyBP-C）被认为调节心肌和心脏收缩。Hanft等人表明，cMyBP-C磷酸化调节鼠透化心肌细胞中功率输出的长度依赖性，这转化为体内Frank-Starling关系。Frank-Starling关系表明，舒张末期容积的增加会逐渐增加健康心脏的心室压和每搏输出量。这种关系受到许多生理输入的调节，并且在人类心力衰竭中经常受到抑制。新出现的证据表明，心肌肌球蛋白结合蛋白C（cMyBP-C）有助于弗兰克-斯塔林的关系。我们测量了多个结构组织水平的收缩特性，以确定cMyBP-C及其磷酸化在调节（1）心肌肌丝功率的肌节长度依赖性和（2）体内Frank-Starling关系中的作用。我们比较了在空白背景下表达野生型cMyBP-C的转基因小鼠，其具有超过50%的磷酸化cMyBP-C（对照）、缺乏cMyBP-C的转基因小鼠（KO）和表达具有丝氨酸-273，-282，-302突变为天冬氨酸在空白背景下，使用丙氨酸（cMyBP-C t3 SD）或丙氨酸（cMyBP-C t3 SA）来分别模拟组成型PKA磷酸化或非磷酸化cMyBP-C。我们观察到一个连续的长度依赖性的功率输出的肌细胞制剂。肌节长度依赖性的功率随着cMyBP-C KO = cMyBP-C t3 SA < Control < cMyBP-C t3 SD的等级顺序而逐渐增加。肌丝强度的长度依赖性至少部分地转移到心脏，其中Frank-Starling关系在cMyBP-C t3 SD小鼠中最陡。这些结果支持cMyBP-C及其磷酸化状态调节肌原纤维功率的肌节长度依赖性的假设，并且这些调节过程在心肌组织的空间水平上翻译以控制心跳到心跳的心室性能。
Cardiac myosin-binding protein C (cMyBP-C) is thought to regulate cardiac muscle and heart contraction. Hanft et al. show that cMyBP-C phosphorylation regulates length dependence of power output in murine permeabilized cardiac myocytes, which translates to in vivo Frank–Starling relationships. The Frank–Starling relationship establishes that elevated end-diastolic volume progressively increases ventricular pressure and stroke volume in healthy hearts. The relationship is modulated by a number of physiological inputs and is often depressed in human heart failure. Emerging evidence suggests that cardiac myosin-binding protein-C (cMyBP-C) contributes to the Frank–Starling relationship. We measured contractile properties at multiple levels of structural organization to determine the role of cMyBP-C and its phosphorylation in regulating (1) the sarcomere length dependence of power in cardiac myofilaments and (2) the Frank–Starling relationship in vivo. We compared transgenic mice expressing wild-type cMyBP-C on the null background, which have ∼50% phosphorylated cMyBP-C (Controls), to transgenic mice lacking cMyBP-C (KO) and to mice expressing cMyBP-C that have serine-273, -282, and -302 mutated to aspartate (cMyBP-C t3SD) or alanine (cMyBP-C t3SA) on the null background to mimic either constitutive PKA phosphorylation or nonphosphorylated cMyBP-C, respectively. We observed a continuum of length dependence of power output in myocyte preparations. Sarcomere length dependence of power progressively increased with a rank ordering of cMyBP-C KO = cMyBP-C t3SA < Control < cMyBP-C t3SD. Length dependence of myofilament power translated, at least in part, to hearts, whereby Frank–Starling relationships were steepest in cMyBP-C t3SD mice. The results support the hypothesis that cMyBP-C and its phosphorylation state tune sarcomere length dependence of myofibrillar power, and these regulatory processes translate across spatial levels of myocardial organization to control beat-to-beat ventricular performance.
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影响因子：
39.3
作者：
JACOB, R;DIERBERGER, B;KISSLING, G
通讯作者：
KISSLING, G
影响因子：
2.9
作者：
Belknap, Betty;Harris, Samantha P.;White, Howard D.
通讯作者：
White, Howard D.
DOI：
10.1098/rspb.1938.0050
发表时间：
1938-10-01
期刊：
PROCEEDINGS OF THE ROYAL SOCIETY SERIES B-BIOLOGICAL SCIENCES
影响因子：
--
作者：
Hill, AV
通讯作者：
Hill, AV
影响因子：
5.5
作者：
Fukuda, N;Wu, YM;Granzier, H
通讯作者：
Granzier, H
影响因子：
5
作者：
Copeland, O'Neal;Sadayappan, Sakthivel;Marston, Steven B.
通讯作者：
Marston, Steven B.