Nicolas Tardif1, Maria Klaude, Lars Lundell, Anders Thorell, Olav Rooyackers. 1. Departments of Anesthesiology and Intensive Care (NT, MK, and OR) and Surgery (LL), Gastrocentrum, Karolinska University Hospital Huddinge and Karolinska Institutet, Stockholm, Sweden, and the Department of Clinical Science, Danderyds Hospital & Department of Surgery, Ersta Hospital, Stockholm, Sweden (AT).
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.
BACKGROUND: In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechanisms in cancerpatients 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 cancerpatients [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 cancerpatients 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 cancerpatients 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 cancerpatients was modified, whereas other proteolytic systems were unchanged. These findings suggest involvement of the autophagic-lysosomal proteolytic system during cancer cachexia development in humans.
Authors: Hawley E Kunz; Jessica M Dorschner; Taylor E Berent; Thomas Meyer; Xuewei Wang; Aminah Jatoi; Rajiv Kumar; Ian R Lanza Journal: J Biol Chem Date: 2020-10-01 Impact factor: 5.157
Authors: Paul T Winnard; Santosh K Bharti; Marie-France Penet; Radharani Marik; Yelena Mironchik; Flonne Wildes; Anirban Maitra; Zaver M Bhujwalla Journal: Cancer Res Date: 2015-12-30 Impact factor: 12.701