Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts.
Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts.
复制标题
DOI：
10.1085/jgp.202213290
复制
发表时间：
2023-05-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
发现心肌肌钙蛋白I的N-末端区域的磷酸化调节肌丝功率输出，并且这种翻译后修饰可以被利用来增加来自人类衰竭心脏的肌丝的功率输出。心脏的泵血能力是由肌丝发电决定的。功率是单位时间内所做的功，用力和速度的乘积来衡量。在肌节水平，这些收缩特性与连接的横桥的数量及其循环速率有关，许多信号传导途径调节一个或两个因素。我们之前表明，在PKA介导的肌原纤维蛋白磷酸化后，啮齿动物透化心肌细胞的功率增加。目前的研究发现，PKA在来自人类衰竭心脏的透化心肌细胞制备物（n = 8）中使功率增加约30%。为了解决PKA效应的肌丝分子特异性，在内源性慢骨骼肌钙蛋白与重组人肌钙蛋白复合物交换之前和之后，在大鼠透化慢收缩骨骼肌纤维中测量机械特性，所述重组人肌钙蛋白复合物含有心脏（c）肌钙蛋白T、肌钙蛋白C和野生型（WT）肌钙蛋白I或在位点Ser 23/24 Asp、Tyr 26 Glu或组合Ser 23/24 Asp和Tyr 26 Glu处的假磷酸化肌钙蛋白I。我们发现cTnI Ser 23/24 Asp、Tyr 26 Glu以及Ser 23/24 Asp和Tyr 26 Glu的组合足以使功率增加约20%。接下来，我们确定Ser 23/24处的假磷酸化cTnI是否足以增加人类衰竭心脏的心肌细胞的能量。在包括cTnI Ser 23/24 Asp的cTnI交换后，来自人衰竭心脏的左心室的透化心肌细胞制备物（n = 6）的功率输出增加约20%。这些结果暗示cTnI N-末端磷酸化作为心肌细胞功率的分子调节剂，并且可以作为小分子治疗的区域靶点，以揭示人类衰竭心脏中的心肌细胞功率储备能力。
Phosphorylation of the N-terminal region of cardiac troponin I was found to regulate myofilament power output, and this posttranslational modification can be leveraged to increase power output in myofilaments from human failing hearts. The heart’s pumping capacity is determined by myofilament power generation. Power is work done per unit time and measured as the product of force and velocity. At a sarcomere level, these contractile properties are linked to the number of attached cross-bridges and their cycling rate, and many signaling pathways modulate one or both factors. We previously showed that power is increased in rodent permeabilized cardiac myocytes following PKA-mediated phosphorylation of myofibrillar proteins. The current study found that that PKA increased power by ∼30% in permeabilized cardiac myocyte preparations (n = 8) from human failing hearts. To address myofilament molecular specificity of PKA effects, mechanical properties were measured in rat permeabilized slow-twitch skeletal muscle fibers before and after exchange of endogenous slow skeletal troponin with recombinant human Tn complex that contains cardiac (c)TnT, cTnC and either wildtype (WT) cTnI or pseudo-phosphorylated cTnI at sites Ser23/24Asp, Tyr26Glu, or the combinatorial Ser23/24Asp and Tyr26Glu. We found that cTnI Ser23/24Asp, Tyr26Glu, and combinatorial Ser23/24Asp and Tyr26Glu were sufficient to increase power by ∼20%. Next, we determined whether pseudo-phosphorylated cTnI at Ser23/24 was sufficient to increase power in cardiac myocytes from human failing hearts. Following cTn exchange that included cTnI Ser23/24Asp, power output increased ∼20% in permeabilized cardiac myocyte preparations (n = 6) from the left ventricle of human failing hearts. These results implicate cTnI N-terminal phosphorylation as a molecular regulator of myocyte power and could serve as a regional target for small molecule therapy to unmask myocyte power reserve capacity in human failing hearts.
登录
查看更多内容
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：
20.1
作者：
Herron, TJ;Korte, FS;McDonald, KS
通讯作者：
McDonald, KS
DOI：
10.1085/jgp.202012770
发表时间：
2021-07-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Hanft LM;Fitzsimons DP;Hacker TA;Moss RL;McDonald KS
通讯作者：
McDonald KS
影响因子：
2.7
作者：
Hinken, Aaron C.;Hanft, Laurin M.;Scruggs, Sarah B.;Sadayappan, Sakthivel;Robbins, Jeffery;Solaro, R. John;McDonald, Kerry S.
通讯作者：
McDonald, Kerry S.
影响因子：
4.8
作者：
Barbato, JC;Huang, QQ;Jin, JP
通讯作者：
Jin, JP