Abnormalities in metabolism leading to loss of muscle mass contribute to the morbidity and mortality of kidney failure. Our long-term goal is to identify uremia-induced mechanisms causing muscle loss in order to devise novel therapies to combat this problem. We have identified new processes that cause muscle protein losses: 1) caspase-3 activation is the initial step that breaks down the complex structure of muscle yielding substrates that are degraded by the ubiquitin system. 2) The trigger that accelerated muscle loss is decreased activity of IRS-1 associated phosphatidylinositol 3-kinase activity (IRS-1-PI3K). Decreased IRS-1- PI3K stimulates caspase-3 and the ubiquitin system, including the critical enzyme, atrogin-1/MAFbx. 3) Physiological levels of glucocorticoids (GC) are absolutely required to activate protein degradation pathways. Thus, we propose a "two hit" process: GC and suppressed insulin responses synergistically suppress IRS-1- PI3K activity and initiate muscle proteolysis. We will test the two hit model using experimental models;mice lacking the insulin or IGF-1 receptor in muscle. We will extend our study to uremia using transgenic mice that exhibit activation of the IRS-1-PI3K pathway (e.g., PTEN deletion, Akt or IGF-1). Specifically, we will: 1) test if there is an essential role for both GC and impaired insulin/IGF-1 responses that stimulates muscle proteolysis in mice with deficiency of the insulin or the IGF-1 receptor or both receptors but only in muscle;2) examine the mechanism for GC- and insulin/IGF-1 deficiency-dependent downregulation of IRS-1-PI3K activity in muscle;and 3) examine how manipulation of PI3K and Akt activities in vivo will change uremia- induced muscle proteolysis using transgenic mice. The significance of our results is that the two-hit model could apply to many conditions because GC and decreased insulin responses are present in many catabolic illnesses,

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK037175-28
Application #
8220781
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Maruvada, Padma
Project Start
1987-09-01
Project End
2016-02-29
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
28
Fiscal Year
2012
Total Cost
$378,730
Indirect Cost
$136,730
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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