Collaborative Research: A New Twist on Muscle Contraction

滑动细丝理论被广泛接受为分离制剂中肌肉收缩的有用模型。然而，该理论未能解释肌肉功能的至关重要的特征。尽管进行了几十年的研究，但对自然运动过程中肌肉力量的预测模型仍然难以捉摸。研究人员将检验这一假说，即肌肉的重要特性可以通过缠绕的细丝假说来解释。这项拟议的工作具有很大的潜力，可以帮助我们理解神经激活和外加力是如何共同决定体内肌肉力量的。研究结果将被整合到丹尼森大学、西北大学和北亚利桑那大学的研究生和/或本科课程中。此外，研究小组将利用丹尼森大学和北亚利桑那大学的计划，招募代表人数不足的研究参与者。研究结果将通过标准的出版机制和不同的公共媒体以及参与工程学、生物力学和生理学领域的跨学科会议向广大受众传播。研究人员将使用MDM小鼠来测试缠绕细丝假说的预测。缠绕假说认为，除了细丝外，Titin还被钙离子激活，跨桥不仅平移和旋转细丝，在等长力发展过程中将弹性能量储存在PEVK titin中。由于肌节几何形状对肌动蛋白激活和缠绕的限制，该假说对刺激和长度变化对肌力的影响做出了独特的定量预测。通过将不同的肌肉纳入拟议的研究，研究人员可以确定肌联蛋白结构和功能的自然变化是否有助于激活和依赖于长度的肌肉特性(例如，双重增强和力抑制/增强)。这些实验将通过将实验结果与模型预测进行比较，来测试Titin的激活和缠绕是否单独或结合在一起，可以解释观察到的肌肉力量。

The sliding filament theory is widely accepted as a useful model of muscle contraction in isolated preparations. However, the theory fails to account for critically important characteristics of muscle function. Despite decades of work, a predictive model of muscle force during natural movements remains elusive. The researchers will test the hypothesis that important properties of muscle can be explained by the winding filament hypothesis. The proposed work has significant potential to inform our understanding of how neural activation and applied forces together determine in vivo muscle force. Results from the research will be integrated into graduate and/or undergraduate courses at Denison University (RUI-eligible), Northwestern University, and Northern Arizona University. In addition, the research team will leverage programs at Denison University and Northern Arizona University for recruiting under-represented participants in research. Results will be disseminated to broad audiences through standard mechanisms of publication and diverse public media, as well as participation in interdisciplinary conferences in the areas of engineering, biomechanics, and physiology.The researchers will use the mdm mouse to test predictions of the winding filament hypothesis. The winding hypothesis claims that, in addition to the thin filaments, titin is activated by Ca2+, and that cross-bridges not only translate but also rotate the thin filaments, storing elastic energy in PEVK titin during isometric force development. Due to constraints of sarcomere geometry on titin activation and winding, the hypothesis makes unique quantitative predictions about the effects of stimulation and length changes on muscle force. By including different muscles in the proposed studies, the researchers can determine whether naturally occurring variation in titin structure and function contributes to activation- and length-dependent muscle properties (e.g., doublet potentiation and force depression/enhancement). The experiments will test whether titin activation and winding, alone or in combination, can account for observed muscle forces by comparing experimental results to model predictions.