Ait-Mou Younss, Zhang Mengjie, Martin Jody L, Greaser Marion L, de Tombe Pieter P
Department of Cell and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 South First Ave, Maywood, IL 60153, United States.
Department of Animal Sciences, Muscle Biology Laboratory, University of Wisconsin - Madison, 1450 Linden Drive, Madison, WI 53706, United States.
Prog Biophys Mol Biol. 2017 Nov;130(Pt B):281-287. doi: 10.1016/j.pbiomolbio.2017.06.009. Epub 2017 Jun 22.
Stretch of myocardium, such as occurs upon increased filling of the cardiac chamber, induces two distinct responses: an immediate increase in twitch force followed by a slower increase in twitch force that develops over the course of several minutes. The immediate response is due, in part, to modulation of myofilament Ca sensitivity by sarcomere length (SL). The slowly developing force response, termed the Slow Force Response (SFR), is caused by a slowly developing increase in intracellular Ca upon sustained stretch. A blunted immediate force response was recently reported for myocardium isolated from homozygous giant titin mutant rats (HM) compared to muscle from wild-type littermates (WT). Here, we examined the impact of titin isoform on the SFR. Right ventricular trabeculae were isolated and mounted in an experimental chamber. SL was measured by laser diffraction. The SFR was recorded in response to a 0.2 μm SL stretch in the presence of [Ca] = 0.4 mM, a bathing concentration reflecting ∼50% of maximum twitch force development at 25 °C. Presence of the giant titin isoform (HM) was associated with a significant reduction in diastolic passive force upon stretch, and ∼50% reduction of the magnitude of the SFR; the rate of SFR development was unaffected. The sustained SL stretch was identical in both muscle groups. Therefore, our data suggest that cytoskeletal strain may underlie directly the cellular mechanisms that lead to the increased intracellular [Ca] that causes the SFR, possibly by involving cardiac myocyte integrin signaling pathways.
心肌的拉伸，比如在心脏腔室充盈增加时发生的情况，会引发两种不同的反应：即刻的收缩力增加，随后是在几分钟内逐渐发展的收缩力缓慢增加。即刻反应部分归因于肌节长度（SL）对肌丝钙敏感性的调节。缓慢发展的力反应，称为慢力反应（SFR），是由持续拉伸后细胞内钙的缓慢增加引起的。最近有报道称，与野生型同窝仔鼠（WT）的肌肉相比，从纯合巨型肌联蛋白突变大鼠（HM）分离出的心肌的即刻力反应减弱。在此，我们研究了肌联蛋白异构体对SFR的影响。分离右心室小梁并将其安装在实验腔室中。通过激光衍射测量SL。在[Ca] = 0.4 mM（该浴液浓度反映了25°C时最大收缩力发展的约50%）的情况下，记录对0.2μm SL拉伸的SFR。巨型肌联蛋白异构体（HM）的存在与拉伸时舒张期被动力的显著降低以及SFR幅度降低约50%相关；SFR的发展速率未受影响。两组肌肉的持续SL拉伸相同。因此，我们的数据表明，细胞骨架应变可能直接构成导致细胞内[Ca]增加从而引起SFR的细胞机制的基础，这可能涉及心肌细胞整合素信号通路。
