The maintenance of muscle mass requires a complex symphony of cellular responses. During muscle atrophy, an imbalance of hormones and cytokines shifts regulatory signaling pathways (e.g., PI3K/Akt) towards protein degradation by increasing the activities of the ubiquitin-proteasome system and caspase-3. These proteolytic responses are unique to skeletal muscle, despite the fact that all tissues are exposed to the same systemic signals. This atrophy program, if unabated, could result in a deleterious loss of muscle proteins. Induction of two muscle -specific E3 ubiquitin ligases, atrogin-1 and MuRF1, has been proposed to be a key part of the atrophy response. The FOXO transcription factors appear to play a key role in the shift towards protein degradation by increasing the transcription of these E3s and possible other proteolytic enzymes (e.g., caspase-3).
Aim 1 will examine how the FOXOs affect protein sythesis and degradation in muscle cells. Studies in Aim 2 will determine if higher atrogin-1 levels increase the degradation of calcineurin (CaN), a key phosphatase in muscle cells. We propose that the decrease in CaN may provide a mechanism to moderate the severity of wasting by removing an enzyme that can activate (i.e., dephosphorylate) the proapoptotic protein BAD;active BAD increases caspase-3 activity (Aim 4). The decrease in CaN could prevent caspase-3 activity from becoming excessive without affecting other proteolytic responses.
Aim 3 will demonstrate that BAD is regulated by multiple signaling pathways and is a critical determinant of caspase-3 activity in muscle. We also propose that the muscle-sparing effects of b2- adrenergic agonists result, in part, from a PKA-dependent increase in BAD phosphorylation and a subsequent reduction in caspase-3 activity (Aim 5). In summary, we believe that FOXO and BAD are key signaling proteins through which diverse physiologic stimuli regulate protein attrition via the ubiquitin- proteasome system and caspase-3, respectively. Our studies will provide evidence that these two proteolytic systems can function independently and as an integrated pathway that allows for close regulation of muscle mass in response to physiologic conditions. New information regarding the mechanisms of muscle atrophy may identify therapeutic targets to reduce morbidity and mortality of chronically ill patients and improve their quality of life.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050740-11
Application #
7668438
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Eggers, Paul Wayne
Project Start
1996-08-01
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2011-07-31
Support Year
11
Fiscal Year
2009
Total Cost
$224,910
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Reddy, Ramesh N; Knotts, Taylor L; Roberts, Brian R et al. (2011) Calcineurin A-? is required for hypertrophy but not matrix expansion in the diabetic kidney. J Cell Mol Med 15:414-22
Russ Price, S; Klein, Janet D (2011) Cyclooxygenase-2 in the kidney: good, BAD, or both? Kidney Int 80:905-907
Zheng, Bin; Ohkawa, Sakae; Li, Haiyan et al. (2010) FOXO3a mediates signaling crosstalk that coordinates ubiquitin and atrogin-1/MAFbx expression during glucocorticoid-induced skeletal muscle atrophy. FASEB J 24:2660-9
Roberts-Wilson, Tiffany K; Reddy, Ramesh N; Bailey, James L et al. (2010) Calcineurin signaling and PGC-1alpha expression are suppressed during muscle atrophy due to diabetes. Biochim Biophys Acta 1803:960-7
Hu, Junping; Du, Jie; Zhang, Liping et al. (2010) XIAP reduces muscle proteolysis induced by CKD. J Am Soc Nephrol 21:1174-83
Price, S Russ; Gooch, Jennifer L; Donaldson, Sue K et al. (2010) Muscle atrophy in chronic kidney disease results from abnormalities in insulin signaling. J Ren Nutr 20:S24-8
Gao, Yongmei; Ordas, Ronald; Klein, Janet D et al. (2008) Regulation of caspase-3 activity by insulin in skeletal muscle cells involves both PI3-kinase and MEK-1/2. J Appl Physiol 105:1772-8
Wang, Xiaonan; Hu, Junping; Price, S Russ (2007) Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells. Am J Physiol Cell Physiol 292:C1874-9
Bailey, James L; Zheng, Bin; Hu, Zhaoyong et al. (2006) Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy. J Am Soc Nephrol 17:1388-94

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