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.

CONCLUSION:

These results favor the clinical feasibility of using Ca-HMB over high doses of leucine for the treatment of cancer cachexia.

• Authors: Kamran A Mirza, Suzette L Pereira, Anne C Voss, Michael J Tisdale
• Journal: Nutrition (Burbank, Los Angeles County, Calif.) (Nutrition) 2014 Jul-Aug Vol. 30 Issue 7-8 Pg. 807-13 ISSN: 1873-1244 [Electronic] United States
• PMID: 24984997 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Lipopolysaccharides
• Muscle Proteins
• Protein Subunits
• Proteoglycans
• Tripartite Motif Proteins
• Ubiquitin
• Valerates
• proteolysis-inducing peptide
• Angiotensin II
• beta-hydroxyisovaleric acid
• Fbxo32 protein, mouse
• SKP Cullin F-Box Protein Ligases
• Trim63 protein, mouse
• Ubiquitin-Protein Ligases
• Proteasome Endopeptidase Complex
• Leucine

Topics

• Angiotensin II
• Animals
• Cachexia (drug therapy, etiology, metabolism)
• Disease Models, Animal
• Leucine (pharmacology, therapeutic use)
• Lipopolysaccharides
• Male
• Mice
• Mice, Inbred Strains
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Muscle Proteins (metabolism)
• Muscle, Skeletal (cytology, drug effects, metabolism)
• Neoplasms (complications, metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Biosynthesis (drug effects)
• Protein Subunits (metabolism)
• Proteoglycans
• Proteolysis (drug effects)
• SKP Cullin F-Box Protein Ligases (metabolism)
• Tripartite Motif Proteins
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (metabolism)
• Valerates (pharmacology, therapeutic use)