Muscle wasting and negative nitrogen balance are debilitating features of many disease states including diabetes, chronic renal failure and cancer. We have recently identified a new gene, atrogin-1, which is expressed specifically in skeletal muscle and is strongly induced when muscle atrophies in various animal models of these diseases. The atrogin-1 protein contains an F-box, suggesting that it may act as a ubiquitin-protein ligase that catalyzes the ubiquitination and degradation of key proteins, leading to muscle wasting. This proposal is an outgrowth of studies which were initiated in Dr. Alfred Goldberg's laboratory, where Dr. Lecker was a postdoctoral fellow, and will now be continued mainly in the independent laboratory of Dr. Lecker. The functions and importance of this novel protein will be clarified by utilizing a combination of genetic and biochemical approaches. Muscle cells in culture will be engineered to inducibly express atrogin-1, so that its effects on muscle growth, differentiation and atrophy can be studied. The mouse atrogin-1 gene will be disrupted to generate a knockout strain where we can test whether mice lacking atrogin-1 can develop muscle atrophy. In an effort to understand how atrogin-1 might promote muscle protein breakdown, we will attempt to identify its targets and cofactors by the yeast two-hybrid approach and biochemical isolation of atrogin-1-associated proteins. Finally, we will develop in vitro assays to measure the ability of atrogin-1 to conjugate ubiquitin to proteins. Elucidating the functions of atrogin-1 will not only help characterize the mechanisms and physiological regulation of muscle protein breakdown but may also allow the development of pharmacological inhibitors that could combat muscle wasting conditions and its associated morbidity (e.g. the uremia in renal failure).

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK062307-05
Application #
7221935
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Mullins, Christopher V
Project Start
2003-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$511,495
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Lecker, Stewart H; Mitch, William E (2011) Proteolysis by the ubiquitin-proteasome system and kidney disease. J Am Soc Nephrol 22:821-4
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Menconi, Michael; Gonnella, Patricia; Petkova, Victoria et al. (2008) Dexamethasone and corticosterone induce similar, but not identical, muscle wasting responses in cultured L6 and C2C12 myotubes. J Cell Biochem 105:353-64
Bdolah, Yuval; Segal, Adam; Tanksale, Preeti et al. (2007) Atrophy-related ubiquitin ligases atrogin-1 and MuRF-1 are associated with uterine smooth muscle involution in the postpartum period. Am J Physiol Regul Integr Comp Physiol 292:R971-6
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Zhao, Jinghui; Brault, Jeffrey J; Schild, Andreas et al. (2007) FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6:472-83
Lecker, Stewart H; Goldberg, Alfred L; Mitch, William E (2006) Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807-19
Sandri, Marco; Lin, Jiandie; Handschin, Christoph et al. (2006) PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 103:16260-5
Skurk, Carsten; Izumiya, Yasuhiro; Maatz, Henrike et al. (2005) The FOXO3a transcription factor regulates cardiac myocyte size downstream of AKT signaling. J Biol Chem 280:20814-23

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