title: Comparison of the anticatabolic effects of leucine and Ca-β-hydroxy-β-methylbutyrate in experimental models of cancer cachexia.
abstract: OBJECTIVE
  Loss of skeletal muscle is the most debilitating feature of cancer cachexia, and there are few treatments available. The aim of this study was to compare the anticatabolic efficacy of L-leucine and the leucine metabolite β-hydroxy-β-methylbutyrate (Ca-HMB) on muscle protein metabolism, both in vitro and in vivo.
  
  
  METHODS
  Studies were conducted in mice bearing the cachexia-inducing murine adenocarcinoma 16 tumor, and in murine C2 C12 myotubes exposed to proteolysis-inducing factor, lipopolysaccharide, and angiotensin II.
  
  
  RESULTS
  Both leucine and HMB were found to attenuate the increase in protein degradation and the decrease in protein synthesis in murine myotubes induced by proteolysis-inducing factor, lipopolysaccharide, and angiotensin II. However, HMB was more potent than leucine, because HMB at 50 μM produced essentially the same effect as leucine at 1 mM. Both leucine and HMB reduced the activity of the ubiquitin-proteasome pathway as measured by the functional (chymotrypsin-like) enzyme activity of the proteasome in muscle lysates, as well as Western blot quantitation of protein levels of the structural/enzymatic proteasome subunits (20 S and 19 S) and the ubiquitin ligases (MuRF1 and MAFbx). In vivo studies in mice bearing the murine adenocarcinoma 16 tumor showed a low dose of Ca-HMB (0.25 g/kg) to be 60% more effective than leucine (1 g/kg) in attenuating loss of body weight over a 4-d period.
  
  
  CONCLUSIONS
  These results favor the clinical feasibility of using Ca-HMB over high doses of leucine for the treatment of cancer cachexia.
authors.affiliation: Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom. Electronic address: K.a.mirza@aston.ac.uk.
authors.forename: Kamran A
authors.initials: KA
authors.lastname: Mirza
authors.affiliation: Abbott Nutrition, Research & Development, Columbus, Ohio, USA.
authors.forename: Suzette L
authors.initials: SL
authors.lastname: Pereira
authors.affiliation: Abbott Nutrition, Research & Development, Columbus, Ohio, USA.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Voss
authors.affiliation: Nutritional Biomedicine, School of Life and Health Sciences, Aston University, Birmingham, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tisdale
mesh_terms: D000804:Angiotensin II; D000818:Animals; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004195:Disease Models, Animal; D007930:Leucine / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000150:complications / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D011509:Proteoglycans; D059748:Proteolysis / Q000187:drug effects; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014631:Valerates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D008070:Lipopolysaccharides; D009124:Muscle Proteins; D021122:Protein Subunits; D011509:Proteoglycans; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; D014631:Valerates; C042057:proteolysis-inducing peptide; D000804:Angiotensin II; C004961:beta-hydroxyisovaleric acid; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D007930:Leucine
keywords: L-Leucine; Muscle; Protein degradation; Protein synthesis; β-hydroxy-β-methylbutyrate, HMB