RUI/Collaborative Research: The Effects of Age related Changes in Muscle Extracellular Matrix on Muscle Performance and Gait

肌肉细胞外基质，肌肉纤维周围的结缔组织，已被证明随着年龄、停用和神经肌肉疾病而改变。这些情况会导致肌肉纤维化--肌肉细胞外基质的病理性增加。这项工作旨在从组织、器官和整个生物体的水平上了解肌肉纤维化的基本功能含义。除了在生物组织的不同水平上研究系统的机制外，该项目还将结合互补的建模和实验方法，以更好地了解纤维化肌肉的基本特性。广泛的科学目标是阐明纤维化对肌肉功能的影响，并研究这种变化与步态和运动缺陷的关系。此外，外联工作将扩大代表性不足群体的研究经验，并帮助制定高中科学课程中的跨学科课程计划。骨骼肌的细胞外基质(ECM)在肌肉纤维和肌束的被动弹性和僵硬中起着关键作用，但ECM的性质变化如何可能影响收缩性能、体内功能和步态仍不清楚。该项目将结合使用成熟的衰老动物模型系统(F344xBN大鼠)的实证研究和建模方法，以检查细胞外基质的重塑如何影响性能。第一个目标将是使用分离的肌束和激光衍射来表征与年龄相关的纤维化如何改变肌肉纤维产生机械功的能力。假说是，细胞外基质硬度的增加限制了肌肉纤维和肌束的径向扩张，从而限制了肌肉执行机械工作的能力。第二个目标是使用高速X射线成像来检查肌肉纤维化如何影响正常运动时的肌肉表现。该项目将测试肌肉僵硬增加限制肌肉以相对较短的长度运行的假设，从而导致体内力量产生的减少。最后，考察了增加被动刚度对步态力学的影响。使用来自大鼠的经验数据来推进动态步态模拟，PI将明确地将被动肌肉僵硬对关节力学和全身性能的孤立影响联系起来。通过将对组织、器官和整个生物体的经验研究与模型模拟相结合，这项工作将阐明ECM特性的变化如何影响生物组织水平的表现。

Muscle extracellular matrix, the connective tissue surrounding muscle fibers, has been shown to change with age, disuse, and neuromuscular disease. These conditions cause muscle fibrosis-a pathological increase in muscle extra cellular matrix. This work aims to understand the basic functional implications of muscle fibrosis at the level of tissues, organs and whole organisms. In addition to examining the mechanics of the system at various levels of biological organization, the project will combine complementary modeling and experimental approaches to better understand the fundamental properties of fibrotic muscle. The broad scientific goal is to elucidate the implications of fibrosis for muscle function, and to examine how such changes relate to deficiencies in gait and movement. In addition, outreach efforts will broaden research experiences for underrepresented groups and aid in the development of interdisciplinary lesson plans in high-school science curricula. The extracellular matrix (ECM) of skeletal muscle is known to play a critical role in the passive elasticity and stiffness of muscle fibers and fascicles, but it remains unclear how variation in the properties of the ECM are likely to affect contractile performance, in vivo function, and gait. The project will integrate empirical studies using a well-established animal model system for aging (F344xBN rats) with modeling approaches to examine how the remodeling of the ECM impacts performance. The first objective will be to use isolated muscle fascicles and laser diffraction to characterize how age-related fibrosis alters the capacity of muscle fibers to produce mechanical work. The hypothesis is that increased ECM stiffness limits a muscle's ability to perform mechanical work by limiting radial expansion of muscle fibers and fascicles. The second objective is to use high-speed x-ray imaging to examine how muscle fibrosis affects muscle performance during normal locomotion. The project will test the hypothesis that increased muscle stiffness restricts muscle to operate at relatively short lengths, resulting in decreased force production in vivo. Finally, an examination of the effects of increasing passive stiffness on gait mechanics. Using empirical data from rats to drive forward dynamic gait simulations, the PIs will explicitly link the isolated effects of passive muscle stiffness on joint mechanics and whole-body performance. By integrating empirical studies of tissues, organs and whole organisms with model simulations the work will elucidate how variation in ECM properties affects performance across levels of biological organization.