title: Suppression of muscle wasting by the plant-derived compound ursolic acid in a model of chronic kidney disease.
abstract: BACKGROUND
  Muscle wasting in chronic kidney disease (CKD) and other catabolic disorders contributes to morbidity and mortality, and there are no therapeutic interventions that regularly and safely block losses of muscle mass. We have obtained evidence that impaired IGF-1/insulin signalling and increases in glucocorticoids, myostatin and/or inflammatory cytokines that contribute to the development of muscle wasting in catabolic disorders by activating protein degradation.
  
  
  METHODS
  Using in vitro and in vivo models of muscle wasting associated with CKD or dexamethasone administration, we measured protein synthesis and degradation and examined mechanisms by which ursolic acid, derived from plants, could block the loss of muscle mass stimulated by CKD or excessive levels of dexamethasone.
  
  
  RESULTS
  Using cultured C2C12 myotubes to study muscle wasting, we found that exposure to glucocorticoids cause loss of cell proteins plus an increase in myostatin; both responses are significantly suppressed by ursolic acid. Results from promoter and ChIP assays demonstrated a mechanism involving ursolic acid blockade of myostatin promoter activity that is related to CEBP/δ expression. In mouse models of CKD-induced or dexamethasone-induced muscle wasting, we found that ursolic acid blocked the loss of muscle mass by stimulating protein synthesis and decreasing protein degradation. These beneficial responses included decreased expression of myostatin and inflammatory cytokines (e.g. TGF-β, IL-6 and TNFα), which are initiators of muscle-specific ubiquitin-E3 ligases (e.g. Atrogin-1, MuRF-1 and MUSA1).
  
  
  CONCLUSIONS
  Ursolic acid improves CKD-induced muscle mass by suppressing the expression of myostatin and inflammatory cytokines via increasing protein synthesis and reducing proteolysis.
authors.affiliation: Nephrology Division, Changhai Hospital, Shanghai, China.|Nephrology Division, Zhejiang Provincial People's Hospital, Hongzhou, China.|Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Rizhen
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Health Education, College of Preventive Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Ji-An
authors.initials: JA
authors.lastname: Chen
authors.affiliation: Nephrology Division, Changhai Hospital, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Michael E. Debakey VA Medical Center, Houston, TX, USA.|Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Sandhya S
authors.initials: SS
authors.lastname: Thomas
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Zhaoyong
authors.initials: Z
authors.lastname: Hu
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D003907:Dexamethasone; D004195:Disease Models, Animal; D008297:Male; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009133:Muscular Atrophy / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D055435:Myostatin / Q000097:blood; D014176:Protein Biosynthesis / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D000097245:Ursolic Acid
chemical_list: D016207:Cytokines; D003907:Dexamethasone; D055435:Myostatin; D014315:Triterpenes; D000097245:Ursolic Acid; C525912:Mstn protein, mouse
keywords: Cachexia; Chronic kidney disease; Muscle wasting; Myostatin; Ursolic acid