Previous studies suggest that sepsis-induced muscle wasting is associated with increased muscle calcium levels and that glucocorticoids are the predominant mediator of sepsis-induced muscle proteolysis. The overall hypothesis of the current project is that glucocorticoids increase muscle calcium levels and that sepsis and glucocorticoids increase muscle proteolysis through calcium-dependent mechanisms. This is tested in 3 specific aims.
Specific Aim 1 tests the hypothesis that sepsis and glucocorticoids increase muscle calcium levels and calcium-calmodulin protein kinase II (CaMK II) and calpain activities.
Specific Aim 2 tests the hypothesis that sepsis- and glucocorticoid-induced activation of the muscle wasting-associated transcription factors C/EBPp and 8 and NF-kB is regulated by increased calcium levels and activation of CaMK II and calpains.
Specific Aim 3 tests the hypothesis that sepsis- and glucocorticoid-induced muscle proteolysis and upregulation of the ubiquitin ligases atrogin-1 arid MuRF1 are regulated by increased calcium levels and activation of CaMK II and calpains. Studies are performed in two models of muscle wasting, i.e., in septic rats and in dexamethasone-treated cultured myotubes. In several previous studies, we have found that sepsis in rats induced by cecal ligation and puncture (CLP) and treatment of cultured myotubes with dexamethasone result in increased protein degradation and upregulated gene expression of the ubiquitin-proteasome-proteolytic pathway. The role of calcium is examined by using the calcium chelator BAPTA or the calcium """"""""antagonists"""""""" verapamil and dantrolene. The roles of CaMK II and calpains are tested by using specific inhibitors or by transfecting myocytes with plasmids expressing the enzymes or the natural calpain inhibitor calpastatin. The project is important because it will provide information about early and initiating mechanisms of sepsis- and glucocorticoid-induced muscle wasting, if our hypothesis is correct, calcium-regulated mechanisms may become important therapeutic targets in the prevention and treatment of muscle wasting in sepsis and other catabolic conditions. Relevance: Patients with sepsis, cancer, or injury suffer loss of muscle mass. Muscle wasting in these and other catabolic conditions contributes significantly to morbidity and mortality. The proposed experiments will define the role of calcium and calcium-regulated mechanisms in the development of muscle-wasting in sepsis. Increased understanding of the mechanisms driving muscle wasting will help improve prevention and treatment of this debilitating condition. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037908-18
Application #
7448585
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Haft, Carol R
Project Start
1987-01-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
18
Fiscal Year
2008
Total Cost
$298,464
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
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

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