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

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，老年肌肉作为一个奇妙的模型，探索收缩性和力传递结构蛋白，包括骨骼肌在自然的，慢性适应状态。与此同时，老年人内在肌肉收缩性能下降的机制尚不清楚。肌肉收缩力可受到钙（Ca 2+）调节力受损或肌动蛋白-肌球蛋白跨桥相互作用中收缩力降低的影响。有一些证据表明，受损的Ca 2+处理，这减少了老年肌肉的激活，从而减少了力量的产生。同样，有证据表明，肌球蛋白亚型随年龄的变化，但是，这是否影响力的生产上的跨桥水平尚未阐明。随着年龄的增长，快速型肌肉纤维的比例面积减少，导致整个肌肉收缩性能变弱，变慢和变弱。收缩功能的丧失，即使是按肌肉质量和纤维类型标准化时，也可能表明跨桥动力学受损。我们预计，交叉桥连接的数量减少和结合状态之间的过渡动力学受损（即，分离的、弱束缚的和强束缚的）将有助于老年时静态和动态肌肉功能的降低。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，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。 拟议的研究计划侧重于调节正常成人衰老中肌肉收缩力的机制。单肌纤维是实现这些目标的理想准备，因为它们允许肌肉的机械，结构和生化特性与局限于其天然环境的收缩蛋白质之间的直接比较。在接下来的五年里，我们（我的HQP和我）将量化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。通过将蛋白质功能与肌肉功能的研究相结合，我们将展示跨桥动力学的变化如何转化为收缩功能的改变。作为细胞收缩功能的介质的跨桥动力学的评估对于获得调节这些精细肌肉特性的机制以及系统如何调节到自然的、慢性适应的状态（即，老化）。

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).