Uremia is often associated with weight loss, reduced muscle mass and a low serum albumin. Our long-term goal is to identify cellular mechanisms causing protein malnutrition in uremia to improve treatment. In rats with chronic renal failure (CRF), we identified metabolic acidosis as a stimulus for accelerated muscle protein degradation. This proteolytic response was confirmed in patients and is now vigorously treated to improve their nutritional status but the mechanism(s) underlying muscle catabolism is unknown. Factors that we identified as activators of the ubiquitin-proteasome (Ub-P'some) Proteolytic pathway in muscle are a low extracellular pH, glucocorticoids and a low insulin level. Important problems to be solved are: first, myofibrillar proteins are not degraded and adding actin blocks myosin degradation by the Ub-P'some system. Our Preliminary Results indicate that the protease, caspase 3, is induced by acidification and plays a role in the early stages of muscle cell proteolysis by degrading myofibrillar proteins and actin to a stage where degradation proceeds via the Ub-P'some pathway. A second problem is how to integrate multiple signals that can activate the Ub-P'some system. We propose that depressed phoshatidylinositol 3-kinase (PI 3-kinase) is a key step as: we find CRF reduces muscle PI 3-kinase activity and insulin (or IGF- 1) blocks caspase 3 activation in muscle cells. A third problem is to understand how signals that initiate muscle proteolysis invariably stimulate transcription of genes encoding components of the Ub-P'some pathway. Since clinical evidence suggests an important role for TNFalpha in causing muscle wasting in CRF, we will examine the opposing actions between glucocorticoids and a TNFalpha-inducible transcription factor, NF-kB, on transcription of the C3 proteasome subunit to understand the requirement for glucocorticoids in stimulating transcription in many catabolic conditions. Finally, we will examine how TNFalpha influences protein degradation in muscle of CRF rats and in cultured muscle cells. Our results will uncover cellular mechanisms regulating protein turnover in uremia and other catabolic conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037175-20
Application #
6825703
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
1987-09-01
Project End
2005-05-31
Budget Start
2004-12-01
Budget End
2005-05-31
Support Year
20
Fiscal Year
2005
Total Cost
$80,695
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Thomas, Sandhya S; Mitch, William E (2017) Parathyroid hormone stimulates adipose tissue browning: a pathway to muscle wasting. Curr Opin Clin Nutr Metab Care 20:153-157
Dong, Jiangling; Dong, Yanjun; Chen, Zihong et al. (2017) The pathway to muscle fibrosis depends on myostatin stimulating the differentiation of fibro/adipogenic progenitor cells in chronic kidney disease. Kidney Int 91:119-128
Dong, Jiangling; Dong, Yanjun; Dong, Yanlan et al. (2016) Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Int J Obes (Lond) 40:434-442
Luo, Jinlong; Liang, Anlin; Liang, Ming et al. (2016) Serum Glucocorticoid-Regulated Kinase 1 Blocks CKD-Induced Muscle Wasting Via Inactivation of FoxO3a and Smad2/3. J Am Soc Nephrol 27:2797-808
Weiner, I David; Mitch, William E; Sands, Jeff M (2015) Urea and Ammonia Metabolism and the Control of Renal Nitrogen Excretion. Clin J Am Soc Nephrol 10:1444-58
Silva, Kleiton Augusto Santos; Dong, Jiangling; Dong, Yanjun et al. (2015) Inhibition of Stat3 activation suppresses caspase-3 and the ubiquitin-proteasome system, leading to preservation of muscle mass in cancer cachexia. J Biol Chem 290:11177-87
Thomas, Sandhya S; Zhang, Liping; Mitch, William E (2015) Molecular mechanisms of insulin resistance in chronic kidney disease. Kidney Int 88:1233-1239
Liang, Ming; Wang, Yun; Liang, Anlin et al. (2015) Impaired integrin ?3 delays endothelial cell regeneration and contributes to arteriovenous graft failure in mice. Arterioscler Thromb Vasc Biol 35:607-15
Xia, Yunfeng; Jin, Xiaogao; Yan, Jingyin et al. (2014) CXCR6 plays a critical role in angiotensin II-induced renal injury and fibrosis. Arterioscler Thromb Vasc Biol 34:1422-8
Hu, Zhaoyong; Klein, Janet D; Mitch, William E et al. (2014) MicroRNA-29 induces cellular senescence in aging muscle through multiple signaling pathways. Aging (Albany NY) 6:160-75

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