Abstract: Our society is becoming more and more sedentary, thereby worsening and accelerating the effects of aging. The central system that is responsible for the beneficial effects of mobility on brain function, cardiac function, metabolism, and other organs is the musculoskeletal system. Without muscle contraction and bone movement, there is no exercise and therefore no beneficial effects on the organism. Exercise appears to delay the negative effects of aging and can ameliorate negative effects of diseases associated with aging. Exercise maintains both muscle and bone mass and it is most likely the maintenance of the health of the musculoskeletal system that is responsible for the health of the organism. The hypothesis to be tested includes: Crosstalk occurs between muscle and bone through systemic factors. The osteocyte is regulated by both mechanical loading and by factors secreted by contracted muscle. In turn, the osteocyte regulates muscle myogenesis and function. Exercise targets the osteocyte and muscle by reducing the negative effects of aging. The specific aims of this program project renewal are 1). Determine how young and old osteocytes regulate myogenesis, muscle mass and function, 2). Determine how muscle protects and maintains osteoblast/osteocyte viability and function, 3). Examine the role of extracellular vesicles in bone-muscle crosstalk, 4). Determine the role of estrogen/β-catenin in muscle-bone crosstalk with aging and 5). Determine if exercise can rescue or reduce the negative effects of aging on bone-muscle crosstalk. These specific aims will be accomplished through a multidisciplinary approach where bone and muscle biologists interact along with engineers and biochemists. This program project focuses on bone-muscle crosstalk utilizing muscle and bone transgenic mouse models, unique bone and muscle cell lines, live cell imaging and intravital imaging capabilities and integration of metabolomics and lipidomics. The projects and their supporting cores are highly integrative and will lead to synergistic interactions where the potential for progress and success is greater than the individual components. Identification of the mechanisms used by muscle and bone to communicate and regulate the musculoskeletal system as a whole and how these are regulated by exercise should lead to interventions for musculoskeletal disease, dysfunction, and disorders and prevent the negative effects of immobilization and aging, not only on the musculoskeletal system, but on the overall health of the individual.