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

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) . mu g protein(-1) . min(-1); P < 0.001] and 115% (5.3 +/- 0.4 compared with 2.5 +/- 0.3 pmol AMC . mu g 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.