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Mechanisms and mediators that are associated with catabolic conditions to impair satellite cell function: role of glucocorticoids

Grant number: 12/03142-8
Support Opportunities:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): September 01, 2012
Effective date (End): August 31, 2013
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Nestor Schor
Grantee:Kleiton Augusto dos Santos Silva
Supervisor: William E. Mitch
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Research place: Baylor College of Medicine, United States  
Associated to the scholarship:11/20109-1 - Role of Previuos Resistance Exercise Training on Renal and Muscle mTOR Signaling in Rats with Diabetes, BP.DR

Abstract

Chronic Kidney Disease (CKD) and Diabetes Mellitus (DM) have become epidemic diseases characterized by metabolic abnormalities and associated with cardiovascular and kidney complications. These catabolic conditions accelerate muscle protein degradation by activating caspase-3 and the ubiquitin-proteasome system (UPS). Several studies have shown that accumulation of the 14kD actin fragment in muscles of animals with accelerated protein degradation is due to catabolic conditions as such DM, CKD, acidosis, angiotensin II and insulin resistance. A type of "stem cell" in muscle is known as the satellite cell. After muscle injury, such as resistance exercise, satellite cells are activated and express the MyoD and myogenin transcription factors, leading to satellite cell proliferation and differentiation. In CKD, muscles of mice show decreased expression of MyoD, myogenin, and embryonic myosin heavy-chain protein (eMyHC) mRNAs, implying that loss of muscle mass is related to defects in the functions of satellite cells. An excess of glucocorticoids frequently accompanies catabolic conditions. This is relevant because glucocorticoids can suppress protein synthesis and raise protein degradation in muscle, contributing to muscle wasting. We hypothesize that mice with CKD or diabetes will have increased production of glucocorticoids leading to overexpression of myostatin in muscle. Synergistically, glucocorticoids and myostatin will stimulate the degradation of MyoD and this in turn, will suppress satellite cell function, ultimately leading to muscle atrophy. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SANTOS SILVA, KLEITON AUGUSTO; DONG, JIANGLING; DONG, YANJUN; DONG, YANLAN; SCHOR, NESTOR; TWEARDY, DAVID J.; ZHANG, LIPING; MITCH, WILLIAM E.. Inhibition of Stat3 Activation Suppresses Caspase-3 and the Ubiquitin-Proteasome System, Leading to Preservation of Muscle Mass in Cancer Cachexia. Journal of Biological Chemistry, v. 290, n. 17, p. 11177-11187, . (12/03142-8)

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