Autophagic-lysosomal pathway is the main proteolytic system modified in the skeletal muscle of esophageal cancer patients

Am J Clin Nutr. 2013 Dec;98(6):1485-92. doi: 10.3945/ajcn.113.063859. Epub 2013 Oct 9.

Abstract

Background: In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechanisms in cancer patients are not fully understood.

Objective: We investigated the involvement of the proteolytic systems (proteasome, autophagic-lysosomal, calpain, and caspase) in muscle wasting during cancer cachexia.

Design: Esophageal cancer patients [n = 14; mean ± SD age: 64.1 ± 6.6 y] and weight-stable control patients undergoing reflux surgery (n = 8; age: 57.5 ± 5.8 y) were included. Enzymatic activities were measured in the vastus lateralis and diaphragm. Protein expressions were also measured in the vastus lateralis of control (n = 7) and cancer (n = 8) patients.

Results: Proteasome, calpain, and caspase 3 activities in the vastus lateralis and diaphragm muscles did not differ between the 2 groups. Cathepsin B and L activities were 90% (± SD) [2.4 ± 0.2 compared with 1.3 ± 0.2 pmol 7-amido-4-methylcoumarin (AMC) · μg protein⁻¹ · min⁻¹; P < 0.001] and 115% (5.3 ± 0.4 compared with 2.5 ± 0.3 pmol AMC · μg protein⁻¹ · min⁻¹; P < 0.001) greater, respectively, in the vastus lateralis of cancer patients than in that of control subjects. We observed (in conjunction with increased lysosomal protease activities) higher microtubule-associated protein 1 light chain 3B-II/I ratios (0.14 ± 0.08 compared with 0.04 ± 0.04) and cathepsin B and L expressions in the vastus lateralis of cancer patients than in that of control subjects (P < 0.05). Protein expression of p62 in the vastus lateralis did not differ between the 2 groups.

Conclusions: The autophagic-lysosomal pathway in the skeletal muscle of cancer patients was modified, whereas other proteolytic systems were unchanged. These findings suggest involvement of the autophagic-lysosomal proteolytic system during cancer cachexia development in humans.

Publication types

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

MeSH terms

  • Aged
  • Autophagy*
  • Biomarkers / metabolism
  • Cachexia / enzymology
  • Cachexia / etiology
  • Cachexia / metabolism*
  • Cathepsin B / metabolism*
  • Cathepsin L / metabolism*
  • Diaphragm / enzymology
  • Diaphragm / metabolism
  • Esophageal Neoplasms / physiopathology*
  • Esophageal Neoplasms / surgery
  • Female
  • Humans
  • Lipid Metabolism
  • Lysosomes / enzymology
  • Lysosomes / metabolism*
  • Male
  • Microtubule-Associated Proteins / metabolism
  • Middle Aged
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / metabolism*
  • Proteolysis
  • Quadriceps Muscle / enzymology
  • Quadriceps Muscle / metabolism
  • Reproducibility of Results
  • Up-Regulation

Substances

  • Biomarkers
  • MAP1LC3B protein, human
  • Microtubule-Associated Proteins
  • CTSB protein, human
  • Cathepsin B
  • CTSL protein, human
  • Cathepsin L