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

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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).