Musculoskeletal microvascular circulations supply nutrients, oxygen and physiological flow to and move waste from muscle and bone. Musculoskeletal complications, induced by reduced microcirculation in the condition during injury and functional disuse (e.g., bedrest and microgravity), have significant physiological effects in muscle atrophy and osteopenia. Exercise such as muscle contraction appears to increase blood flow to the skeletal tissues, i.e., bone and muscle. Musculo-dynamics induced bone fluid flow is proposed as a critical mediator in initiating and regulating osteonal adaptation. Using oscillatory pressurized marrow fluid flow stimuli, the physiological fluid stimulus was found to initiate new bone formation and reduce intracortical bone porosities caused by disuse, even in the absence of direct tissue strain. While bone remodeling was demonstrated to be sensitive to high rate of dynamic physiological stimulation, the role of fluid flow in both bone and muscle perhaps explains, at least in part, the cellular response mechanism to anabolic stimuli. In the work proposed, we will examine the general hypothesis that skeletal musculocirculation, mediated at dynamic functional stimulation, serves as a dynamic muscle pump and a critical mediator for bone fluid flow, which controls and promotes osteogenic and muscular adaptation. Indeed, improving our understanding the roles of muscular dynamics (e.g., frequency and magnitude of muscle contraction), circulations, and fluid flow through bone may help to devise a biomechanically based intervention for treating osteoporosis, muscle atrophy, and accelerating fracture healing or promoting bony ingrowth into prostheses. In this application, the goal will be achieved by a series of sub-hypotheses and specific aims: (1) Dynamic interstitial fluid flow can be initiated and enhanced by functional contraction of skeletal muscle. Functional muscle contraction serves as a dynamic pump to generate intramedullary pressure and regulates venous return, which initiate fluid flow in bone. (2) Bone fluid flow induced by musculo-dynamic stimulation can initiate surface adaptive response and inhibit intracortical bone loss in a disuse bone. The adaptive response will be sensitive to the rate of loading patterns. (3) Osteogenic response to anabolic fluid flow stimuli induced by muscle-pump is dependent on generated fluid pressure magnitude and loading duration. (4) The potentials of dynamic patterns of muscle stimuli can initiate muscular adaptation, in which loads induced at the physiological level will increase capillary density and substantially increase blood flow in muscle, while overloading will cause partial musculovascular atrophy following bone bloodflow ischemia. (5) Fluid infiltration in muscle and bone can be optimized by insertion of rest preiod during dynamic loading, which reduce the fluid saturation and improve perfusion. (6) The osteogenic potentials response to fluid flow stimuli is initiated by osteoblastic activation of bone lining cells, following a daily but short duration (e.g., <10 days) of loading. Ultrastructural osteoblastic features of cell and nuclei will be examined via histomorphometric analysis of cell area, nuclear area, cell number, cell and nuclei shapes, in which associated fluid components will be identified.
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