Research Project
10291071
PROJECT SUMMARY/ABSTRACT Skeletal muscle and bone integrity progressively declines as we age, largely due to decreased levels of growth factors and physical activity. Insulin-like Growth Factor-I (IGF-I) is a major mediator of muscle growth and regeneration, specifically through the regulation of muscle stem cells (satellite cells) in order to repair damaged muscle fibers. During aging, the gradual decrease in IGF-I levels contributes to the failure of the muscle growth and regenerative capacity further causing loss of muscle mass and function; however, which cell in the muscle provides the critical source of IGF-I have yet to be established. Thus, Aim 1 of this fellowship is to determine the critical source of IGF-I in the muscle milieu that promotes muscle growth and regeneration, with novel mouse models that ablate cell-specific IGF-I production, developed by the PI. The hypertrophic response of the muscle beds from IGF-I has the potential to provide the benefits of mechanical loading to the bone. Indeed, muscular contraction facilitates mechanical stimulation to the bone; however, physical inactivity in the aging population decreases the ability of bones to sense and respond to mechanical forces, which contributes to the decline in bone density and strength. Osteocytes are mature bone cells that sense and respond to mechanical stimuli from the muscle, further directing the activity of osteoclasts (bone resorption) and osteoblasts (bone formation) for bone remodeling. Perlecan (PLN) is essential for osteocyte mechanotransduction; however, PLN availability decreases with age due to decreased mechanotransduction. Nonetheless, the effects of bone remodeling due to decreased PLN expression in the osteocytic matrix remains unknown. Additionally, PLN is known to sequester numerous growth factors; however, whether PLN serves as a growth factor reservoir to induce bone formation is entirely unexplored. Therefore, Aim 2 of this proposal is to determine if PLN plays a role as a growth factor reservoir in the ECM surrounding osteocytes that further enhances bone remodeling. This proposal will investigate the mechanism of growth factors necessary to increase muscle and bone mass, in order to strengthen the musculoskeletal system in the aging community. In the F99 phase of this proposed research, the PI will be trained and mentored on muscle physiology to test the hypothesis that IGF-I ablation in satellite cells slows the proliferation rate and impairs muscle growth and regeneration. Her work will be performed at the University of Florida, which houses the Myology Institute providing rich resources from extensive muscle expertise. During the K00 phase, the PI will perform her work with bone experts at the Indiana Center for Musculoskeletal Health to test the hypothesis that PLN serves as a reservoir for growth factors in the osteocytic matrix for bone remodeling. The completion of this work will provide mechanistic insight into the growth factors necessary to increase muscle and bone mass, and will shed light to potential factors that interact in the muscle-bone unit. This fellowship will aid in a successful transition from pre-doctoral to post-doctoral training, and develop a well-trained junior scientist poised to independently investigate the muscle-bone interactions in aging and disease.
