Cross-bridge and non-cross-bridge based mechanisms of single muscle fibre mechanical function in human senescence

人类衰老过程中单肌纤维力学功能的跨桥和非跨桥机制

• 批准号: RGPIN-2016-03829
• 负责人: Power, Geoffrey
• 金额: $ 2.4万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684617
• 关键词: Cross; bridge; non; cross; based

Human senescence is associated with a loss of muscle mass and alterations to the structural components of the neuromuscular system, resulting in diminished contractile function of the entire aged system. Thus, aged muscle serves as a fantastic model to explore contractility and force-transmitting structural proteins that comprise skeletal muscle in a natural, chronically-adapted state. Meanwhile, the mechanisms responsible for diminished intrinsic muscle contractile properties in old age are not clear. Muscle contractility can be affected by compromised calcium (Ca2+) regulation of force or by a decrease in contractile force in the actin-myosin based cross-bridge interactions. There is some evidence of impaired Ca2+ handling, which reduces activation of aged muscles and thus reduces force production. Similarly, there is evidence that myosin isoforms change with age; however, whether this affects force production on the cross-bridge level has not been elucidated. With aging, there is a reduction in the proportional area of fast type muscle fibres, resulting in weaker, slower, and less powerful whole-muscle contractile properties. The loss of contractile function, even when normalized to muscle mass and fibre type, likely indicates impairments in cross-bridge kinetics. We expect that a decreased number of cross-bridge attachments and impaired transitional kinetics between binding states (i.e., detached, weakly and strongly bound) will contribute to reductions in static and dynamic muscle function in old age. Despite a wealth of data on the loss of muscle mass and whole body function, little is known about aging on the cellular and molecular level. Therefore, the focus of this NSERC-supported research program will be to examine the relationship between cellular and molecular changes and force production in aged muscle.****The proposed research program focuses on mechanisms that regulate muscle contractility in normal adult aging. Single muscle fibres are the ideal preparation to achieve these goals as they allow direct comparisons among mechanical, structural and biochemical properties of muscle with the contractile proteins confined to their native environment. Over the course of the next five years, we (my HQP and I) will quantify the contributions of active cross-bridge based mechanisms and passive structural proteins to static and dynamic force production across fibre types of young and old adults. By integrating studies of protein function with muscle function, we will demonstrate how changes in cross-bridge kinetics translate into altered contractile function. The evaluation of cross-bridge kinetics as mediators of cellular contractile function is important to gain a fundamental understanding of the mechanisms regulating these fine muscle properties and how the system adjusts to a natural, chronically adapted state (i.e., aging).**

人类衰老与肌肉质量的损失和神经肌肉系统结构成分的改变有关，导致整个老年系统的收缩功能减弱。因此，衰老的肌肉可以作为一个奇妙的模型来探索骨骼肌在自然、长期适应状态下的收缩性和力传递结构蛋白。同时，导致老年肌肉固有收缩特性减弱的机制尚不清楚。肌肉收缩力可能受到钙（Ca2+）调节力受损或肌动蛋白-肌球蛋白交叉桥相互作用中收缩力下降的影响。有一些证据表明Ca2+处理受损，这减少了老化肌肉的激活，从而减少了力量的产生。同样，有证据表明肌球蛋白同型体随着年龄的增长而改变；然而，这是否会影响跨桥水平的力产生尚未阐明。随着年龄的增长，快速型肌纤维的比例面积减少，导致整个肌肉的收缩性能变弱、变慢、变弱。收缩功能的丧失，即使按肌肉质量和纤维类型进行标准化处理，也可能表明过桥动力学受损。我们预计，减少的过桥附着物数量和结合状态（即分离，弱和强结合）之间的过渡动力学受损将有助于老年肌肉静态和动态功能的降低。尽管有大量关于肌肉质量和全身功能损失的数据，但在细胞和分子水平上对衰老知之甚少。因此，这个nserc支持的研究项目的重点将是研究细胞和分子变化与老年肌肉力量产生之间的关系。****提出的研究计划侧重于正常成人衰老过程中调节肌肉收缩力的机制。单个肌纤维是实现这些目标的理想准备，因为它们允许将肌肉的机械、结构和生化特性与局限于其天然环境的收缩蛋白进行直接比较。在接下来的五年里，我们（我的HQP和我）将量化基于主动跨桥机制和被动结构蛋白对年轻人和老年人纤维类型的静态和动态力产生的贡献。通过整合蛋白质功能与肌肉功能的研究，我们将展示过桥动力学的变化如何转化为收缩功能的改变。评估过桥动力学作为细胞收缩功能的介质对于获得调节这些精细肌肉特性的机制以及系统如何调整到自然的、长期适应的状态（即衰老）的基本理解是重要的