Comparison of the anticatabolic effects of leucine and Ca-β-hydroxy-β-methylbutyrate in experimental models of cancer cachexia

Nutrition. Jul-Aug 2014;30(7-8):807-13. doi: 10.1016/j.nut.2013.11.012. Epub 2013 Dec 4.

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.

Keywords: L-Leucine; Muscle; Protein degradation; Protein synthesis; β-hydroxy-β-methylbutyrate, HMB.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Cachexia / drug therapy*
  • Cachexia / etiology
  • Cachexia / metabolism
  • Disease Models, Animal
  • Leucine / pharmacology
  • Leucine / therapeutic use*
  • Lipopolysaccharides
  • Male
  • Mice
  • Mice, Inbred Strains
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / metabolism
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Neoplasms / complications
  • Neoplasms / 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
  • Valerates / therapeutic use*

Substances

  • 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