Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Norway (J.L., Y.H., M.L., M.R., T.R.K., M.F., P.A.N., I.E.S., O.M.S., I.G.L., W.E.L.).
KG Jebsen Center for Cardiac Research, University of Oslo, Norway (J.L., Y.H., M.L., M.R., T.R.K., M.F., I.E.S., O.M.S., I.G.L., W.E.L.).
Circ Res. 2023 Jul 21;133(3):255-270. doi: 10.1161/CIRCRESAHA.123.322588. Epub 2023 Jul 4.
Increasing cardiomyocyte contraction during myocardial stretch serves as the basis for the Frank-Starling mechanism in the heart. However, it remains unclear how this phenomenon occurs regionally within cardiomyocytes, at the level of individual sarcomeres. We investigated sarcomere contractile synchrony and how intersarcomere dynamics contribute to increasing contractility during cell lengthening.
Sarcomere strain and Ca were simultaneously recorded in isolated left ventricular cardiomyocytes during 1 Hz field stimulation at 37 °C, at resting length and following stepwise stretch.
We observed that in unstretched rat cardiomyocytes, differential sarcomere deformation occurred during each beat. Specifically, while most sarcomeres shortened during the stimulus, ≈10% to 20% of sarcomeres were stretched or remained stationary. This nonuniform strain was not traced to regional Ca disparities but rather shorter resting lengths and lower force production in systolically stretched sarcomeres. Lengthening of the cell recruited additional shortening sarcomeres, which increased contractile efficiency as less negative, wasted work was performed by stretched sarcomeres. Given the known role of titin in setting sarcomere dimensions, we next hypothesized that modulating titin expression would alter intersarcomere dynamics. Indeed, in cardiomyocytes from mice with titin haploinsufficiency, we observed greater variability in resting sarcomere length, lower recruitment of shortening sarcomeres, and impaired work performance during cell lengthening.
Graded sarcomere recruitment directs cardiomyocyte work performance, and harmonization of sarcomere strain increases contractility during cell stretch. By setting sarcomere dimensions, titin controls sarcomere recruitment, and its lowered expression in haploinsufficiency mutations impairs cardiomyocyte contractility.
心肌拉伸时心肌细胞收缩的增加是心脏中弗兰克-斯塔尔机制的基础。然而，在心肌细胞内，在单个肌节的水平上，这种现象如何在区域内发生尚不清楚。我们研究了肌节收缩的同步性以及肌节间动力学如何在细胞伸长过程中增加收缩力。
在 37°C 下，通过 1 Hz 场刺激，在静息长度和逐步拉伸后，同时记录分离的左心室心肌细胞中的肌节应变和 Ca。
我们观察到，在未拉伸的大鼠心肌细胞中，在每次跳动时都会发生不同的肌节变形。具体来说，虽然大多数肌节在刺激期间缩短，但约 10%至 20%的肌节被拉伸或保持静止。这种非均匀应变不是由于区域 Ca 差异引起的，而是由于收缩期拉伸的肌节的静息长度较短和产生的力较低。细胞的伸长募集了额外的缩短肌节，这增加了收缩效率，因为拉伸肌节所做的负功减少了。鉴于 titin 在设定肌节尺寸方面的已知作用，我们接下来假设调节 titin 表达会改变肌节间动力学。事实上，在 titin 单倍不足的小鼠心肌细胞中，我们观察到静息肌节长度的变异性更大，缩短肌节的募集减少，以及在细胞伸长过程中工作性能受损。
分级肌节募集指导心肌细胞的工作性能，肌节应变的协调增加了细胞拉伸过程中的收缩力。通过设定肌节尺寸，titin 控制肌节募集，其在单倍不足突变中的表达降低会损害心肌细胞的收缩力。
