Abstract

Previous studies by the investigator suggest that muscle catabolism seen during sepsis is the result of protein breakdown, specifically in myofibrillar protein. Glucocorticoids, tumor necrosis factor (TNF), and interleukin-1 (IL-1) mediate some of these metabolic changes. The proposed studies are designed to test the following hypotheses: 1) sepsis upregulates the activity and expression of the 20S proteosome in the energy dependent ubiquitin proteolytic pathway, 2) the ubiquitin pathway is regulated in part by glucocorticoids and/or cytokines, 3) muscle catabolism in sepsis reflects stimulated ubiquitin activity. They will use a cecal ligation and puncture model with sham operated animals as controls. Total and myofibrillar protein breakdown will be measured in incubated muscles. Muscle levels of ubiqutin and ubiquitin message will be determined by northern and western blotting techniques. This group also plans to characterize mRNA expression in sepsis by the differential display technique. The ultimate goal of the project is to gain further insight into the exact mechanisms of sepsis-induced muscle catabolism with elucidation of the specific roles of glucocorticoids and cytokines.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037908-10
Application #
2905343
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Laughlin, Maren R
Project Start
1987-01-01
Project End
2000-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221

  Publications

Alamdari, Nima; Aversa, Zaira; Castillero, Estibaliz et al. (2013) Acetylation and deacetylation--novel factors in muscle wasting. Metabolism 62:1-11
Aversa, Zaira; Alamdari, Nima; Castillero, Estibaliz et al. (2013) CaMKII activity is reduced in skeletal muscle during sepsis. J Cell Biochem 114:1294-305
Castillero, Estibaliz; Alamdari, Nima; Aversa, Zaira et al. (2013) PPAR?/? regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting. PLoS One 8:e59726
Castillero, Estibaliz; Alamdari, Nima; Lecker, Stewart H et al. (2013) Suppression of atrogin-1 and MuRF1 prevents dexamethasone-induced atrophy of cultured myotubes. Metabolism 62:1495-502
Aversa, Zaira; Alamdari, Nima; Castillero, Estibaliz et al. (2012) ?-Hydroxy-?-methylbutyrate (HMB) prevents dexamethasone-induced myotube atrophy. Biochem Biophys Res Commun 423:739-43
Alamdari, Nima; Aversa, Zaira; Castillero, Estibaliz et al. (2012) Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism. Biochem Biophys Res Commun 417:528-33
Alamdari, Nima; Toraldo, Gianluca; Aversa, Zaira et al. (2012) Loss of muscle strength during sepsis is in part regulated by glucocorticoids and is associated with reduced muscle fiber stiffness. Am J Physiol Regul Integr Comp Physiol 303:R1090-9
Chamberlain, Wei; Gonnella, Patricia; Alamdari, Nima et al. (2012) Multiple muscle wasting-related transcription factors are acetylated in dexamethasone-treated muscle cells. Biochem Cell Biol 90:200-8
Smith, Ira J; Aversa, Zaira; Hasselgren, Per-Olof et al. (2011) Calpain activity is increased in skeletal muscle from gastric cancer patients with no or minimal weight loss. Muscle Nerve 43:410-4
Aversa, Zaira; Alamdari, Nima; Hasselgren, Per-Olof (2011) Molecules modulating gene transcription during muscle wasting in cancer, sepsis, and other critical illness. Crit Rev Clin Lab Sci 48:71-86

Showing the most recent 10 out of 110 publications