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。尽管取得了这一进展，但预测肌肉力量在自然运动过程中如何变化的目标仍然难以实现。该项目将通过(1)检验假设，即当肌肉激活时从肌浆网释放钙时，巨大的弹性Titin蛋白的长度和硬度发生变化，以及(2)基于该假设开发肌肉的计算机模型，从而促进对肌肉收缩的理解。一只携带titin基因缺失的突变小鼠将被用来检验这一假设。这项研究将包括：(1)凝胶电泳法估计突变基因中Titin的分子量，(2)力水平实验表征肌原纤维、单纤维和整个肌肉中依赖于激活的Titin的弹性性质，(3)建立包含Titin钙激活的肌肉模型，以及(4)比较不同突变基因之间运动学和能量学的行为研究。这项工作的更广泛影响包括：(1)神经科学、工程学和计算机科学方面的本科生、研究生和博士后学者的跨学科培训，(2)代表不足的学生的参与，以及(3)公共宣传，包括当地高中教师和公共科学和技术磁石学校的学生参与研究项目。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，改进神经肌肉骨骼模拟，了解神经肌肉疾病的原因和潜在的治疗方法，并启发功能更像动物肌肉的执行器和假体的设计。

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.