Is Titin an Exponential Spring in Active Muscle?

在过去的一个世纪里，生理学家在阐明肌肉收缩的分子机制方面取得了显著的进展。尽管取得了这些进展，但预测肌肉力量在自然运动中如何变化的目标仍然难以捉摸。该项目将通过(1)测试假设，即肌肉激活时钙从肌浆网释放时，巨大的弹性titin蛋白的长度和刚度会发生变化，(2)基于这一假设开发肌肉的计算机模型，从而促进对肌肉收缩的理解。携带titin基因缺失的突变小鼠将被用来验证这一假设。这项研究将包括：(1)凝胶电泳来估计突变基因型中titin的分子量；(2)力杆实验来表征肌原纤维、单纤维和整个肌肉中titin的激活依赖弹性特性；(3)建立一个肌肉模型，其中包括titin的钙活化；(4)行为学研究来比较突变基因型的运动运动学和能量学。这项工作的广泛影响包括：(1)对神经科学、工程和计算机科学领域的本科生、研究生和博士后学者的跨学科培训；(2)弱势学生的参与；(3)公众外展，包括当地高中教师和公共科技磁铁学校的学生参与研究项目。研究结果将通过在不同媒体上发表和参加计算机科学、工程和生物学领域的跨学科会议来传播。这项研究有可能改变我们对肌肉激活过程的理解，改善神经肌肉骨骼模拟，为神经肌肉疾病的病因和潜在治疗提供信息，并启发设计功能更像动物肌肉的致动器和假肢。

During the past century, physiologists have made remarkable progress in elucidating the molecular mechanisms of muscle contraction. Despite this progress, the goal of predicting how muscle force changes during natural movements has remained elusive. This project will advance the understanding of muscle contraction by (1) testing the hypothesis that the length and stiffness of the giant, elastic titin protein changes when calcium is released from the sarcoplasmic reticulum upon muscle activation and (2) developing a computer model of muscle based on this hypothesis. A mutant mouse that carries a deletion in the titin gene will be used to test the hypothesis. This research will involve: (1) gel electrophoresis to estimate molecular weights of titin in mutant genotypes, (2) force-lever experiments to characterize activation-dependent elastic properties of titin in myofibrils, single fibers and whole muscles, (3) development of a muscle model that incorporates calcium activation of titin, and (4) behavioral studies to compare kinematics and energetics of locomotion across mutant genotypes. The broader impacts of this work include: (1) interdisciplinary training of undergraduate, graduate, and post-doctoral scholars in neuroscience, engineering, and computer science, (2) participation of under-represented students, and (3) public outreach including participation in the research project by local High School teachers and students from a public science and technology magnet school. Results will be disseminated through publication in diverse media and participation in interdisciplinary conferences in the areas of computer science, engineering, and biology. This research has the potential to transform our understanding of the process of muscle activation, improve neuro-musculoskeletal simulations, inform causes and potential cures for neuromuscular diseases, and inspire the design of actuators and prostheses that function more like animal muscles.