Mechanisms underlying mechanical properties of muscle-tendon units

摘要 肌-腱单元力学特性的机制 骨骼肌的萎缩、虚弱和损伤被广泛认为是与年龄相关的 身体虚弱，但随着年龄的增长，肌肉和肌腱的细胞外基质（ECM）变化的重要性 我们对此知之甚少。初步数据显示，随着年龄的增长，肌腱的机械性能发生了巨大的变化， 在肌腱的肌肉端刚度显著增加，但在骨端变化最小。的 TA肌腱的力学性能随着老化发生广泛的变化， 胶原蛋白含量肌腱功能特性的区域性变化与 潜在的结构可能有助于缺乏明确的关系，迄今为止，生化和 生物力学性能因此，我们的目标是澄清以下机制： 沿着肌腱的机械性能差异，以及（ii）机械性能随老化的变化，以及 以确定肌腱变化对肌肉功能和损伤敏感性的影响。工作 假设是：（i）肌腱力学性能的区域差异是由于区域 胶原含量和蛋白多糖表达的变化导致ECM结构的差异 以及（ii）随着老化，整个肌腱的组成变得与最近区域的组成相似 骨，导致组织变得更硬，整体可伸展性更低， 收缩引起的肌肉纤维损伤。实验将在胫骨前肌（TA）上进行 成年（8月龄）、中年（24 月龄）和老年（33月龄）Fisher X Brown Norway大鼠。具体目标是：1。确定影响 老化对肌张力单位被动力学性能的影响以及肌腱刚度与肌肉之间的相互作用 收缩期间的纤维长度，2.阐明机制的区域差异，机械 沿着肌腱的性能和随着老化发生的肌腱机械性能的变化，以及3. 评估先前主动缩短对由延长收缩（LC）引起的力缺陷的影响。 来自成年和老年大鼠肌肉的透化单纤维。为了实现这些目标，我们的方法将是： (i)在拉伸过程中对沿着MTU的应力-应变关系进行高分辨率光学测量 在没有激活的情况下以及在有和没有拉伸的肌肉激活期间，（ii）执行彻底的区域性运动， 分析肌腱的蛋白质和基因表达、胶原含量和交联以及ECM结构 建立有意义的结构-功能关系，以及（iii）应用于最大限度地激活透化 单纤维从TA肌肉的大鼠，预拉伸缩短运动的跨度，在幅度和 速度，目标1中建立的肌腱的伸展特性，以确定对肌肉功能的影响 和对损伤的敏感性的变化的机械环境的纤维， 肌腱特性的改变。叙事 与公共卫生的相关性是基于对肌肉和肌腱损伤的易感性增加的影响 随着年龄的增长，身体虚弱的发展。虚弱导致不动和福尔斯， 限制独立生活能力的关键因素。我们的项目将进一步了解的贡献 随着年龄的增长，肌腱和肌纤维的机械性能发生变化， 肌肉骨骼损伤阐明老年人结构和功能变化的潜在机制， 肌肉-肌腱单元将提高延迟虚弱的发作和进展的可能性。

Abstract Mechanisms underlying mechanical properties of muscle-tendon units Atrophy, weakness, and injury of skeletal muscle are widely recognized as major contributors to age-related physical frailty, but the importance of changes with aging in extracellular matrix (ECM) of muscle and tendon are poorly understood. Preliminary data show dramatic changes in tendon mechanical properties with aging, with a marked increase in stiffness at the muscle end of the tendon but minimal change at the bone end. The extensive changes with aging in mechanical properties of TA tendons occur with no major change in total collagen content. The regional variation in tendon functional properties coupled with regional variation in underlying structure may contribute to the lack thus far of clear relationships between biochemical and biomechanical properties. Therefore, our goals are to clarify the mechanisms underlying (i) regional differences in mechanical properties along tendons and (ii) changes in mechanical properties with aging, and to determine the impact of tendon changes on muscle function and susceptibility to injury. The working hypotheses are that (i) regional differences in tendon mechanical properties are due to regional variation in collagen content and proteoglycan expression resulting in differences in ECM structure and (ii) with aging, the composition of the entire tendon becomes similar to that of the region nearest bone, causing the tissue to be stiffer and less extensible overall and increasing the likelihood of contraction-induced injury to muscle fibers. Experiments will be performed on tibialis anterior (TA) muscle-tendon units (MTU) and permeabilized single muscle fibers of adult (8 months), middle aged (24 months), and old (33 months) Fisher X Brown Norway rats. The Specific Aims are: 1. determine the impact of aging on passive mechanical properties of MTUs and the interaction between tendon stiffness and muscle fiber length during contraction, 2. elucidate mechanisms underlying the regional differences in mechanical properties along tendons and the changes in tendon mechanical properties that occur with aging, and 3. evaluate the effects of prior active shortening on force deficits caused by lengthening contractions (LCs) of permeabilized single fibers from muscles of adult and old rats. To address the Aims, our approach will be to (i) make high resolution optical measurements of stress-strain relationships along MTUs during stretches without activation and during muscle activation with and without stretch, (ii) perform thorough regional analyses of protein and gene expression, collagen content and cross-linking, and ECM structure of tendons to establish meaningful structure-function relationships, and (iii) apply, to maximally activated permeabilized single fibers from TA muscles of rats, pre-stretch shortening movements that span, in both amplitude and speed, the extension properties of tendons established in Aim 1 to determine the impact on muscle function and susceptibility to injury of alterations in the mechanical environment of fibers that are unavoidably created by changes in tendon properties. Narrative The relevance to public health is based on the impact of increasing susceptibility to muscle and tendon injury as contributors to the development with aging of physical frailty. Frailty causes immobility and falls and is a key factor limiting the ability to live independently. Our project will further understanding of the contribution of changes with aging in the mechanical properties of tendons and muscle fibers to the increased susceptibility to musculoskeletal injury. Clarifying mechanisms underlying changes with aging in the structure and function of muscle-tendon units will improve the likelihood of delaying the onset and progression of frailty.