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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013798-13
Application #
7097919
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Williams, John
Project Start
1989-01-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
13
Fiscal Year
2006
Total Cost
$333,085
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Allouh, Mohammed Z; Yablonka-Reuveni, Zipora; Rosser, Benjamin W C (2008) Pax7 reveals a greater frequency and concentration of satellite cells at the ends of growing skeletal muscle fibers. J Histochem Cytochem 56:77-87
Kirkpatrick, Lisa J; Allouh, Mohammed Z; Nightingale, Chantale N et al. (2008) Pax7 shows higher satellite cell frequencies and concentrations within intrafusal fibers of muscle spindles. J Histochem Cytochem 56:831-40

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