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

人的衰老与肌肉质量的丧失和神经肌肉系统结构成分的改变有关，导致整个衰老系统的收缩功能减弱。因此，衰老的肌肉是探索收缩能力和传递力量的结构蛋白的极好模型，这些结构蛋白组成了处于自然的、长期适应状态的骨骼肌。同时，导致老年固有肌肉收缩特性减弱的机制尚不清楚。在肌动蛋白-肌球蛋白的跨桥相互作用中，肌肉的收缩能力可以受到力的调节或收缩力量的降低的影响。有一些证据表明，钙离子处理能力受损，这会减少衰老肌肉的激活，从而减少力量的产生。同样，有证据表明肌球蛋白亚型随年龄变化；然而，这是否会影响跨桥水平的力量产生还没有阐明。随着年龄的增长，快型肌肉纤维的比例面积会减少，导致整个肌肉的收缩性能更弱、更慢、更弱。收缩功能的丧失，即使当正常化为肌肉质量和纤维类型时，也可能表明跨桥动力学的损害。我们预计，跨桥连接数量的减少和结合状态(即分离的、弱结合的和强结合的)之间的过渡动力学受损将导致老年静态和动态肌肉功能的下降。尽管有大量关于肌肉质量和全身功能丧失的数据，但对细胞和分子水平上的衰老知之甚少。因此，NSERC支持的这项研究计划的重点将是研究衰老肌肉中细胞和分子变化与力量产生之间的关系。*拟议的研究计划侧重于正常成年人衰老过程中肌肉收缩能力的调节机制。单一的肌肉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自然环境的收缩蛋白质进行直接比较。在接下来的五年里，我们(我的HQP和我)将量化基于主动跨桥的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量产生的贡献。通过整合蛋白质功能和肌肉功能的研究，我们将展示跨桥动力学的变化如何转化为改变的收缩功能。评估跨桥动力学作为细胞收缩功能的中介，对于从根本上理解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)是重要的。

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).**