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).
Am J Clin Nutr. 2013 Dec;98(6):1485-92. doi: 10.3945/ajcn.113.063859. Epub 2013 Oct 9.
In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechanisms in cancer patients are not fully understood.
We investigated the involvement of the proteolytic systems (proteasome, autophagic-lysosomal, calpain, and caspase) in muscle wasting during cancer cachexia.
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.
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.
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.
在癌症恶病质中，肌肉消耗与发病率和死亡率有关。癌症患者的肌肉消耗机制尚未完全阐明。
我们研究了蛋白水解系统（蛋白酶体、自噬溶酶体、钙蛋白酶和半胱天冬酶）在癌症恶病质期间肌肉消耗中的作用。
纳入 14 例食管癌患者（平均年龄±标准差：64.1±6.6 岁）和 8 例接受反流手术的体重稳定对照患者（年龄：57.5±5.8 岁）。测量股外侧肌和膈肌的酶活性。还测量了对照组（n=7）和癌症组（n=8）患者股外侧肌的蛋白表达。
2 组患者股外侧肌和膈肌的蛋白酶体、钙蛋白酶和半胱天冬酶 3 活性无差异。组织蛋白酶 B 和 L 活性分别高 90%（±标准差）[2.4±0.2 比 1.3±0.2 pmol 7-氨基-4-甲基香豆素（AMC）·μg 蛋白⁻¹·min⁻¹；P<0.001]和 115%（5.3±0.4 比 2.5±0.3 pmol AMC·μg 蛋白⁻¹·min⁻¹；P<0.001]，股外侧肌中的组织蛋白酶 B 和 L 活性在癌症患者中明显高于对照组。我们观察到（结合溶酶体蛋白酶活性增加）微管相关蛋白 1 轻链 3B-II/I 比值（0.14±0.08 比 0.04±0.04）和股外侧肌中的组织蛋白酶 B 和 L 表达更高在癌症患者中明显高于对照组（P<0.05）。股外侧肌中的 p62 蛋白表达在 2 组间无差异。
癌症患者骨骼肌中的自噬溶酶体途径发生改变，而其他蛋白水解系统未改变。这些发现表明，在人类癌症恶病质的发展过程中，自噬溶酶体蛋白水解系统参与其中。
