It is well established that mechanical stimuli play a central role in the regulation of muscle mass and that maintenance of muscle mass contributes to disease prevention and quality of life; however, the mechanisms involved in converting mechanical signals into the molecular events that control this process are not well understood. For example, recent work has established that a rapamycin-sensitive mechanism (presumably mTOR signaling) is necessary for mechanically-induced growth; yet, the molecular components of this pathway have not been clearly defined. Furthermore, the mechanically-induced signaling events that promote the activation of the rapamycin-sensitive pathway are not known. In an effort to better understand the mechanically-induced rapamycin-sensitive pathway, we propose to use an ex-vivo mechanical stimulator in conjunction with various pharmocological and molecular tools to address the following aims 1) determine the upstream molecules involved in the activation of mechanically-induced rapamycin-sensitive pathway, 2) assess the role of mTOR in the mechanically-induced rapamycin-sensitive pathway and 3) elucidate the mechanically-induced mTOR signaling mechanism(s). This work will help define how mechanical stimuli activate the rapamycin-sensitive pathway and will provide fundamental information for future studies aimed at understanding how mechanical information is converted into the biochemical events that regulate muscle mass.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR052240-02
Application #
7061699
Study Section
Special Emphasis Panel (ZRG1-F10 (20))
Program Officer
Boyce, Amanda T
Project Start
2005-03-10
Project End
2007-03-09
Budget Start
2006-03-10
Budget End
2007-03-09
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Hornberger, Troy Alan; Sukhija, Kunal Balu; Wang, Xiao-Rong et al. (2007) mTOR is the rapamycin-sensitive kinase that confers mechanically-induced phosphorylation of the hydrophobic motif site Thr(389) in p70(S6k). FEBS Lett 581:4562-6
Hornberger, Troy Alan; Sukhija, Kunal Balu; Chien, Shu (2006) Regulation of mTOR by mechanically induced signaling events in skeletal muscle. Cell Cycle 5:1391-6
Hornberger, T A; Chu, W K; Mak, Y W et al. (2006) The role of phospholipase D and phosphatidic acid in the mechanical activation of mTOR signaling in skeletal muscle. Proc Natl Acad Sci U S A 103:4741-6