Skeletal muscle undergoes rapid growth during the earlier phase of postnatal life and declines in mass and strength upon aging. Satellite cells are the myogenic precursors in the postnatal muscle, participating in myofiber growth and repair. Gaining insight into how the dynamics of myofiber growth is regulated is a critical step toward the future development of therapies aimed at reducing age-related muscle atrophy. The proposed investigation will examine the involvement of the fibroblast growth factor (FGF) system during satellite cell differentiation and muscle growth. The overall hypothesis of the proposal is that FGF receptor 4 (FGFR4) mediates specific aspects of FGF signaling during satellite cell differentiation and myofiber growth in the postnatal environment.
The specific aims of the proposal are: 1. To investigate the role of FGFR4 during differentiation of adult myoblasts. 2. The investigate the role of FGFR4 in myofiber growth. 3. To analyze the dynamics of muscle regeneration in mice lacking FGFR4. A comprehensive approach of cell culture and in vivo studies will be undertaken. For functional studies, a retroviral-based expression vector will be developed in which FGFR4 dimerization/activation is induced by a synthetic drug. The expression of this inducible FGFR4 in myoblasts from mice lacking FGFR4 will provide a tightly regulated system for investigating the role of the FGF system during differentiation of myoblasts and formation of myotubes. The in vivo studies will utilize a synchronized system of muscle injury and regeneration to investigate the role of FGFR4 in a physiological relevant model of myogenesis. Assays to be used in the studies include immunocytochemistry, Western blotting, RT-PCR and proteomics. The proposed investigation will contribute to a better understanding of satellite cell dynamics and muscle growth, and can prove important for muscle rehabilitation strategies during disease and aging.
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