Levosimendan’s Effects on Length-Dependent Activation in Murine Fast-Twitch Skeletal Muscle

Michael Haug, Mena Michael, P. Ritter, Larisa Kovbasyuk, Maria Eleni Vazakidou, O. Friedrich
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Abstract

Levosimendan’s calcium sensitizing effects in heart muscle cells are well established; yet, its potential impact on skeletal muscle cells has not been evidently determined. Despite controversial results, levosimendan is still expected to interact with skeletal muscle through off-target sites (further than troponin C). Adding to this debate, we investigated levosimendan’s acute impact on fast-twitch skeletal muscle biomechanics in a length-dependent activation study by submersing single muscle fibres in a levosimendan-supplemented solution. We employed our MyoRobot technology to investigate the calcium sensitivity of skinned single muscle fibres alongside their stress–strain response in the presence or absence of levosimendan (100 µM). While control data are in agreement with the theory of length-dependent activation, levosimendan appears to shift the onset of the ‘descending limb’ of active force generation to longer sarcomere lengths without notably improving myofibrillar calcium sensitivity. Passive stretches in the presence of levosimendan yielded over twice the amount of enlarged restoration stress and Young’s modulus in comparison to control single fibres. Both effects have not been described before and may point towards potential off-target sites of levosimendan.
左西孟旦对小鼠快肌腱长度依赖性活化的影响
左西孟旦在心肌细胞中的钙敏化作用已得到证实,但其对骨骼肌细胞的潜在影响尚未得到明确确定。尽管结果存在争议,但人们仍然认为左西孟旦会通过非靶点(肌钙蛋白 C 以外)与骨骼肌相互作用。为了补充这一争论,我们在一项长度依赖性激活研究中,通过将单个肌纤维浸没在添加了左西孟旦的溶液中,调查了左西孟旦对快肌骨骼肌生物力学的急性影响。我们利用 MyoRobot 技术研究了带皮单肌纤维的钙敏感性,以及它们在左西孟旦(100 µM)存在或不存在时的应力-应变反应。虽然对照组数据与长度依赖性激活理论一致,但左西孟旦似乎将主动发力 "下降肢 "的起始点转移到了更长的肌节长度上,而没有明显改善肌纤维的钙敏感性。与对照组单纤维相比,左西孟旦存在时的被动拉伸产生的恢复应力和杨氏模量扩大了两倍多。这两种效应以前从未描述过,可能指向左西孟旦的潜在脱靶位点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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