Mechanisms Underlying Local and Systemic Effects of Massage

The loss of skeletal muscle mass is a common symptom associated with diseases such as cancer, AIDS, diabetes, and congestive heart failure, and with aging. Muscle atrophy is associated with poor disease prognosis and decreased quality of life and therefore, maintaining muscle size and reducing the loss of muscle during disuse atrophy is of vital significance. Mechanical stimulation of muscle, such as during resistance exercise, stimulates protein synthesis that increases muscle protein content, and muscle size. We showed that mechanical stimulation applied to skeletal muscle in the form of massage is an effective mechanotherapy in rats, since it leads to a shift in protein turnover favoring anabolism, attenuation of muscle loss and enhanced regrowth after disuse-induced atrophy. Whether the same positive effect of massage occurs in humans is currently unknown, but would be extremely beneficial for skeletal muscle and overall health in case where resistance exercise is contraindicated or not feasible. In addition to the direct anabolic effects on the massaged rat muscle, we showed an equally beneficial response on the homologous muscle in the contralateral non-massaged limb. This novel finding indicated the existence of indirect mechanisms that could have profound systemic effects beyond the massaged muscle. Extracellular vesicles (EVs) are lipid membrane-bound vesicles released from cells with the ability to modulate function of cells from which they are released, as well as in cells with which they fuse. As such EVs are likely mediators of the well-documented but poorly-understood effects of massage in humans on the brain and other organs, such as relief of pain, anxiety or depression or changes in immunity. Therefore, the goal of this proposal is to determine anabolic effects of massage in human muscle, and to identify whether EVs released with massage are candidates for beneficial effects of this mechanotherapy on muscle as well as other organs. In Aim 1 we will address the following hypothesis: Massage acts as a mechanotherapy by attenuating muscle atrophy through a shift in protein biogenesis towards anabolism in humans. Using a novel massage device we will apply mechanical load to muscle undergoing atrophy through unilateral lower limb suspension and muscle size as well as protein synthesis and degradation will be determined. In Aim 2 we will test the hypothesis that massage attenuates the loss of EVs during atrophy by enhancing EV biogenesis in muscle. We will measure EVs and their miRNA cargo in the serum, and markers of EV biogenesis in muscle of human subjects from Aim 1. Results from this study will indicate not only whether mechanotherapy, such as massage, can attenuate atrophy and enhance anabolic processes during disuse, but also determine whether EVs are a candidate mechanism for the overall health benefits of massage. This application directly addresses the goals set out in the following program announcement from the National Center for Complementary and Integrative Health: PA-18-322 Health: Fundamental Science Research on Mind and Body Approaches (R21).